UNITED
STATES
ENVIRONMENTAL
PROTECTION
AGENCY
WASHINGTON,
D.
C.
20460
OFFICE
OF
PREVENTION,
PESTICIDES
AND
TOXIC
SUBSTANCES
MEMORANDUM
July
10,
2006
SUBJECT:
Sodium
Cyanide
Revised
HED
Risk
Assessment
for
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
PC
Code
No.
074002;
DP
Barcode
No.
318015
FROM:
Becky
Daiss
Environmental
Health
Scientist
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

THROUGH:
Susan
V.
Hummel
Branch
Senior
Scientist
Reregistration
Branch
4
Health
Effects
Division
(
7509C)

TO:
Wilhelmena
Livingston
Chemical
Review
Manager
Reregistration
Branch
1
Special
Review
and
Registration
Division
(
7508C)

Attached
is
Health
Effects
Division's
(
HED's)
revised
risk
assessment
of
sodium
cyanide
for
purposes
of
issuing
a
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
for
this
active
ingredient.
The
risk
assessment
has
been
revised
to
incorporate
new
residue
data
submitted
by
the
registrant
and
water
monitoring
data
provided
by
the
Arizona
Department
of
Environmental
Quality.
The
disciplinary
science
chapters
and
other
supporting
documentation
are
incorporated
into
the
risk
assessment
or
included
as
appendices
as
follows:

Hazard
Identification
Assessment;
Bill
Dykstra
­
Section
4
and
Appendices
1
&
2
Residue
Chemistry
Assessment;
Thurston
Morton
(
D30275,
6/
29/
06)
Dietary
Exposure
and
Risk
Assessment;
Becky
Daiss
­
Section
6
Occupational
and
Residential
Exposure
Assessment,
David
Jaquith
(
D318017,
4/
4/
06)
Drinking
Water
Assessment;
Faruque
Khan
(
D318020,
2/
7/
06)
Page
2
of
44
TABLE
OF
CONTENTS
pg.
1.0
EXECUTIVE
SUMMARY
.............................................................................................
4
2.0
INGREDIENT
PROFILE................................................................................................
8
2.1
Summary
of
Registered
and
Proposed
Uses
.....................................................................
8
2.2
Structure,
Nomenclature
and
Physical/
Chemical
Properties
..............................................
9
3.0
METABOLISM
ASSESSMENT.....................................................................................
9
3.1
Comparative
Metabolic
Profile
........................................................................................
9
3.1.1
Metabolism
in
Mammals.......................................................................................
9
3.1.2
Plant
Metabolism
...............................................................................................
10
3.1.3
Livestock
Metabolism
.......................................................................................
10
3.2
Environmental
Degradation
..........................................................................................
10
3.3
Metabolites
and
Degradates
..........................................................................................
11
3.4
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
...........................
11
4.0
HAZARD
CHARACTERIZATION/
ASSESSMENT
....................................................
11
4.1
Hazard
Characterization
...............................................................................................
11
4.2
FQPA
Hazard
Considerations
.......................................................................................
19
4.2.1
Adequacy
of
the
Toxicity
Data
Base
..................................................................
19
4.2.2
Evidence
of
Neurotoxicity
.................................................................................
19
4.2.3
Developmental
Toxicity
Studies
........................................................................
21
4.2.4
Reproductive
Toxicity
Studies
...........................................................................
23
4.2.5
Pre­
and/
or
Postnatal
Toxicity
............................................................................
25
4.2.6
Recommendation
for
a
Developmental
Neurotoxicity
Study
...............................
25
4.3
FQPA
Safety
Factor
......................................................................................................
25
4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
...................................................
26
4.4.1
Acute
Reference
Dose
­
General
Population.......................................................
26
4.4.2
Chronic
Reference
Dose.....................................................................................
27
4.4.3
Dermal
Absorption.............................................................................................
29
4.4.4
Dermal
Exposure
All
Durations..........................................................................
29
4.4.5
Inhalation
Exposure
All
Durations......................................................................
29
4.4.6
Margins
of
Exposure..........................................................................................
30
4.4.7
Recommendation
for
Aggregate
Exposure
Risk
Assessments
.............................
30
4.4.8
Classification
of
Carcinogenic
Potential..............................................................
30
4.4.9
Summary
of
Endpoints
Selected
for
Risk
Assessment
.........................................
31
4.5
Endocrine
Disruption.....................................................................................................
31
5.0
PUBLIC
HEALTH
DATA............................................................................................
32
6.0
DIETARY
EXPOSURE
ASSESSMENT
......................................................................
32
6.1
Dietary
Profile
...............................................................................................................
32
6.1.1
Magnitude
of
the
Residue
in
Plants
and
Animals.................................................
32
Page
3
of
44
6.1.2
Residue
Analytical
Method.................................................................................
33
6.2
Drinking
Water
Profile...................................................................................................
33
6.3
Dietary
Exposure
and
Risk.............................................................................................
33
7.0
OCCUPATIONAL
EXPOSURE
AND
RISK................................................................
36
7.1
Regulatory
Standards.....................................................................................................
36
7.2
Exposure
Monitoring
Study...........................................................................................
36
7.3
Inhalation
Exposure
and
Risk.........................................................................................
37
7.4
Dermal
Exposure
and
Risk.............................................................................................
38
8.0
AGGREGATE
EXPOSURE
AND
RISK
......................................................................
38
9.0
CUMULATIVE
RISK...................................................................................................
38
10.0
DATA
NEEDS..............................................................................................................
38
10.1
Residue
Chemistry
Data
Requirements...........................................................................
38
10.2
Toxicology
Data
Requirements......................................................................................
39
APPENDICES
1.0
GUIDELINE
TOXICOLOGY
DATA
SUMMARY.......................................................
40
2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
...............................................................
41
3.0
REFERENCES..............................................................................................................
41
Page
4
of
44
1.0
EXECUTIVE
SUMMARY
This
assessment
provides
information
to
support
the
issuance
of
a
risk
management
decision
document
known
as
a
Tolerance
Reassessment
Eligibility
Decision
(
TRED)
Document
for
sodium
cyanide.
EPA's
pesticide
reregistration
process
provides
for
the
review
of
older
pesticides
(
those
initially
registered
prior
to
November
1984)
under
the
Federal
Insecticide,
Fungicide,
and
Rodenticide
Act
(
FIFRA)
to
ensure
that
they
meet
current
scientific
and
regulatory
standards.
The
process
considers
the
human
health
and
ecological
effects
of
pesticides
and
incorporates
a
reassessment
of
tolerances
(
pesticide
residue
limits
in
food)
to
ensure
that
they
meet
the
safety
standard
established
by
the
Food
Quality
Protection
Act
(
FQPA)
of
1996.
This
document
addresses
the
exposures
and
risks
associated
with
dietary,
drinking
water,
and
residential
uses
of
cyanide.
Occupational
exposures
were
partially
addressed
in
Reregistration
Eligibility
Decision
(
RED)
for
Sodium
Cyanide
published
in
1994.
Occupational
exposures
not
addressed
in
the
RED
are
also
assessed
in
this
document.

Use
Profile
Sodium
cyanide
is
used
as
a
predacide/
rodenticide
and
as
a
pesticide.
As
a
predacide/
rodenticide,
it
is
used
as
a
single
dose
poison
in
the
M­
44
ejector
device
to
control
animals
that
prey
upon
livestock
and
threatened
or
endangered
species
or
that
are
vectors
of
communicable
disease.
For
application,
each
capsule
is
loaded
into
an
ejector
mechanism
of
an
M­
44
device
which
has
been
pounded
into
the
ground
for
use.
The
capsule
holder
is
treated
with
a
scent
used
to
attract
canids
to
the
unit.
When
an
animal
tugs
at
the
capsule
holder,
a
springdriven
plunger
ejects
the
sodium
cyanide
capsule
into
its
mouth.
This
product
is
limited
to
use
only
by
trained
and
certified
applicators
under
the
direct
supervision
of
a
government
agency.

As
an
insecticide,
sodium
cyanide
is
used
a
source
of
hydrocyanic
gas
for
quarantine
fumigation
of
surface
pests
on
citrus.
Currently,
there
are
no
active
registrations
for
sodium
cyanide
with
food/
feed
uses.
However,
there
is
one
Special
Local
Needs
(
SLN)
food/
feed
use
registration
for
sodium
cyanide.
The
SLN
end­
use
product
is
formulated
as
a
granular
containing
98%
sodium
cyanide
as
the
active
ingredient
(
ai).
Sodium
cyanide
is
applied
to
citrus
as
a
postharvest
fumigant.
It
used
as
a
source
of
hydrogen
cyanide
gas.
Sodium
cyanide
is
used
in
California
to
control
red
scale
on
fresh
market
citrus
bound
for
Arizona.
It
is
applied
by
professional
applicators
only.
A
tolerance
for
residues
of
the
insecticide
hydrogen
cyanide
from
postharvest
fumigation
as
a
result
of
application
of
sodium
cyanide
is
established
at
50
ppm
in
or
on
citrus
fruit
(
40
CFR
§
180.130).
There
are
no
products
available
for
residential
application.
OPP's
Biological
and
Economical
Analysis
Division
(
BEAD)
estimates
that
approximately
2800
pounds
of
sodium
cyanide
are
used
annually
on
agricultural
crops
(
i.
e.,
fresh
citrus
commodities)
in
California
(
personal
communication,
Bill
Chism,
BEAD).
Page
5
of
44
Regulatory
History
Sodium
Cyanide
is
a
FIFRA
List
C
reregistration
pesticide.
The
1994
RED
assessed
only
the
use
of
sodium
cyanide
as
a
predacide/
rodenticide.
The
Agency
issued
a
Data
Call­
In
(
DCI)
for
sodium
cyanide
in
September,
1992
requiring
additional
product
chemistry
and
ecological
effects
data.
The
1994
RED
reflects
a
reassessment
of
all
data
submitted
in
response
to
the
1992
DCI.
The
1994
RED
determined
that
the
data
were
sufficient
to
allow
the
Agency
to
assess
the
registered
predacide
uses
of
sodium
cyanide
and
to
determine
that
sodium
cyanide
could
be
used
without
resulting
in
unreasonable
adverse
effects
to
humans
and
the
environment.
This
TRED
addresses
the
FQPA
requirement
for
reassessment
of
tolerances
for
hydrogen
cyanide
and
provides
an
assessment
of
worker
exposure
associated
with
use
of
sodium
cyanide
as
a
source
of
hydrocyanic
gas
for
fumigation
of
surface
pests
on
citrus.

Hazard
Identification
The
toxicology
database
for
hydrogen
cyanide
is
incomplete.
No
guideline
studies
are
available.
All
of
the
critical
studies
are
cited
from
the
open
literature.
Data
on
all
forms
of
cyanide
(
e.
g.,
hydrogen,
sodium,
potassium
cyanide
etc.)
have
been
used
to
identify
hydrogen
cyanide
toxicity
for
this
assessment.
Hydrogen
cyanide
is
extremely
acutely
toxic
by
all
exposure
routes.

All
forms
of
cyanide,
hydrogen,
sodium,
and
potassium,
are
extremely
acutely
toxic
by
the
oral
route.
Based
on
an
analysis
of
case
history
data
the
lowest
fatal
oral
dose
of
hydrogen
cyanide
for
an
average
adult
human
is
estimated
by
FDA
to
be
1
mg/
kg.
The
lowest
reported
fatal
dose
of
cyanide
(
unspecified
form)
in
humans
was
estimated
to
be
0.56
mg/
kg
based
on
incidence
data
published
in
1938.
The
acute
oral
fatal
dose
of
potassium
cyanide
in
rats
is
10­
15
mg/
kg,
which
is
equivalent
to
4­
6
mg/
kg
hydrogen
cyanide.
Results
of
clinical
trials
of
Laetrile
to
treat
cancer
also
provide
evidence
of
the
acute
oral
toxicity
of
hydrogen
cyanide.
Laetrile,
also
known
as
amygdalin,
is
a
plant
compound
that
produces
cyanide.
Use
of
Laetrile
has
been
shown
to
produce
side
effects
of
cyanide
poisoning 
which
can
produce
a
range
of
symptoms,
including
death.
In
a
clinical
trial
of
Laetrile
to
treat
human
cancer,
the
single
dose
of
0.5
g
of
amygdalin
was
determined
to
be
minimally
toxic;
a
single
dose
of
0.5
g
of
amygdalin
is
equivalent
to
0.4
mg/
kg
hydrogen
cyanide/
day.
The
double
dose
(
two
0.5
g
doses
at
an
administration)
was
generally
regarded
as
frankly
toxic
producing
increased
blood
levels
and
associated
increase
in
the
incidence
and
severity
of
some
of
the
toxic
signs
and
symptoms.

The
dose­
effect
curve
of
the
acute
inhalation
effects
in
humans
is
steep.
Slight
effects
occur
at
exposure
levels
of
20­
40
mg/
m3,
150
mg/
m3
is
likely
to
be
fatal
within
30
minutes,
200
mg/
m3
is
likely
to
be
fatal
after
10
minutes,
and
300
mg/
m3
is
immediately
fatal.

An
average
LD50
value
for
human
dermal
exposure
is
estimated
to
be
100
mg/
kg
HCN
(
Toxicity
Category
I).
Air
concentrations
of
7000­
12,000
mg/
m3
HCN
were
estimated
to
be
fatal
after
a
5
minute
exposure
of
workers
with
self­
contained
respirators
without
effective
skin
Page
6
of
44
protection.
Cyanides
are
weakly
irritating
to
the
skin
and
eye.
No
data
are
available
on
sensitizing
properties.

The
primary
effects
of
acute
cyanide
exposure
in
humans
are
central
nervous
system
and
cardiovascular
disturbances.
Typical
signs
of
acute
cyanide
poisoning
include
tachypnea,
headache,
vertigo,
lack
of
motor
coordination,
weak
pulse,
cardiac
arrhythmias,
vomiting,
stupor,
convulsions,
and
coma.

Hydrogen
cyanide
exhibits
relatively
low
subchonic
and
chronic
toxicity
by
the
oral
route.
In
a
13
week
repeated
dose
toxicity
study
in
which
sodium
cyanide
was
administered
in
the
drinking
water,
there
were
no
mortalities,
no
clinical
signs,
and
no
histopathological
effects
in
the
brain,
thyroid,
or
other
organs
of
rats
and
mice
exposed
to
doses
up
to
12.5
and
26
mg/
kg/
day.
A
2­
year
rat
feeding
study
with
hydrogen
cyanide
fumigated
food
containing
residues
up
to
10.8
mg/
kg/
day
showed
no
treatment­
related
effects.
In
this
2­
year
study,
rats
ingested
2
to
3
times
the
fatal
acute
dose
of
hydrogen
cyanide
each
day
throughout
their
lifetime
without
any
measurable
effects.
Significantly,
animals
in
the
subchronic
and
chronic
studies
showed
definite
increases
in
thiocyanate
concentrations
indicating
that
metabolic
detoxification
of
hydrogen
cyanide
had
occurred.
Thiocyanate
is
the
less
toxic
primary
metabolite
of
cyanide.
Hydrogen
cyanide
is
readily
converted
to
thiocyanate
in
the
liver
by
the
enzyme
rhodanese.
This
metabolic
conversion
is
the
major
detoxification
mechanism
for
hydrogen
cyanide.
Results
of
both
animal
and
human
FDA
studies
indicate
that
as
long
as
the
oral
intake
of
hydrogen
cyanide
does
not
exceed
the
body

s
detoxification
mechanisms
via
the
formation
of
thiocyanate,
hydrogen
cyanide
can
be
ingested
in
the
form
of
dietary
residues
for
prolonged
periods
without
harm.

There
are
neurotoxicity,
developmental
and
reproductive
studies
available
with
naturally
occurring
cyanides
or
cyanide
salts
in
the
open
literature.
However,
there
are
no
EPA
guideline
studies
of
these
types
of
studies
available.
Based
on
literature
studies,
neurotoxic
effects
are
a
major
occurrence
across
species
from
exposure
to
cyanide
in
its
various
forms.
There
are
no
developmental
or
reproductive
toxicity
studies
for
hydrogen
cyanide.
Developmental
and
reproductive
studies
with
other
forms
of
cyanide
were
available
and
reviewed
for
this
assessment.
The
weight
of
the
evidence
of
available
data
indicates
that
cyanide
induces
developmental
effects
only
at
doses
or
concentrations
that
are
overtly
toxic
to
the
maternal
animals.

Because
there
are
no
EPA
guideline
neurotoxicity,
developmental
and
reproductive
studies
available,
an
assessment
of
FQPA
hazard
considerations
are
based
on
the
available
open
literature
citations.
Based
on
the
available
data,
there
was
no
qualitative
or
quantitative
increased
susceptibility
in
postnatal
offspring
toxicity
and
there
is
a
low
degree
of
concern
for
residual
uncertainties
for
pre
and/
or
post­
natal
susceptibility.
Therefore,
it
is
recommended
that
the
FQPA
safety
factor
be
reduced
to
1x
for
the
hydrogen
cyanide
risk
assessment.

There
are
no
guideline
studies
and
no
available
open
literature
studies
on
the
carcinogenic
potential
of
cyanide.
However,
acute
lethal
effects
of
cyanide
likely
preclude
the
need
for
Page
7
of
44
carcinogenic
evaluation.
Hydrogen
cyanide
has
been
evaluated
for
mutagenic
potential
with
mixed
results.

Cyanide
gas
and
salts
are
rapidly
absorbed
following
inhalation
and
oral
exposure.
They
are
more
slowly
absorbed
by
dermal
exposure.
Animal
studies
have
shown
that
cyanide
does
not
accumulate
in
the
blood
and
tissues
following
chronic
oral
exposure.
Cyanide
metabolites
are
mainly
excreted
in
the
urine,
with
small
amounts
excreted
through
the
lungs
(
ATSDR,
2004).
Following
inhalation,
cyanide
is
rapidly
distributed
throughout
the
body,
with
measurable
levels
detected
in
all
organs.

Cyanide
is
a
rapid
acting
blocker
of
oxygen
utilization
at
the
cellular
level.
Hydrogen
cyanide
binds
with
cytochrome
oxidase
(
a
ferric
enzyme)
in
the
electron
transport
system
and
inhibits
the
exchange
of
oxygen
from
the
blood
to
the
tissues
by
the
mechanism
of
competitive
inhibition.

Dose
Response
Assessment
Toxicological
endpoints
were
selected
for
dietary
and
occupational
exposure
via
inhalation,
the
relevant
scenarios
for
exposure
to
hydrogen
cyanide
for
this
TRED.
The
acute
RfD
for
the
general
population
was
selected
based
on
published
data
from
a
clinical
trial
of
amygdalin
(
Laetrile)
to
treat
human
cancer.
Hydrogen
cyanide
is
extremely
acutely
toxic
at
doses
lower
than
doses
at
which
chronic
effects
are
observed.
Therefore,
the
acute
endpoint
is
considered
protective
for
chronic
toxicity
and
a
chronic
RfD
was
not
selected.
An
inhalation
exposure
endpoint
for
all
durations
was
selected
from
a
subchronic
hydrogen
cyanide
inhalation
toxicity
study
in
rats
based
on
the
effect
of
mortality.

An
uncertainty
factor
(
UF)
of
100
was
applied
to
the
acute
RfD
based
on
application
of
a
10X
for
intraspecies
variations,
and
10X
for
lack
of
a
LOAEL,
steep
dose­
response
curve,
and
severity
of
toxic
effect.
The
target
level
of
concern
(
LOC)
or
margin
of
exposure
(
MOE)
for
occupational
exposure
via
inhalation
is
30X
(
3X
interspecies
factor
and
10x
intraspecies
factor).

Exposure/
Risk
Assessment
and
Risk
Characterization
Risk
assessments
were
conducted
for
acute
dietary
and
occupational
exposure
pathways
only
based
on
label
prescribed
uses.
Chronic
dietary
exposure
was
not
assessed
because
hydrogen
cyanide
is
severely
acutely
toxic
at
doses
lower
than
those
at
which
chronic
effects
are
observed
i.
e.,
protecting
for
acute
effects
will
also
protect
against
chronic
toxicity.
Drinking
water
exposures
were
not
assessed
because
the
Environmental
Fate
and
Effects
Division
(
EFED)
does
not
anticipate
significant
exposure
from
hydrogen
cyanide
in
surface
or
ground
water
based
on
the
use
pattern.
An
aggregate
assessment
of
risk
from
the
combined
food
and
non­
food
exposures
was
not
conducted
because
there
are
no
residential
uses
of
hydrogen
cyanide.
Residential
exposures
resulting
from
citrus
fumigation
are
not
expected
based
on
monitoring
data
from
the
single
facility
at
which
hydrogen
cyanide
fumigation
occurs.
HED
conducted
a
somewhat­
refined
Page
8
of
44
acute
probabilistic
dietary
assessment
for
hydrogen
cyanide.
Recently
submitted
field
trial
data
were
used
to
assess
potential
exposure
and
risk
from
consumption
of
citrus
treated
with
hydrogen
cyanide.
HED's
acute
dietary
assessment
indicates
that
acute
dietary
exposure
estimates
are
below
HED's
level
of
concern.
Data
from
a
worker
exposure
inhalation
monitoring
study
on
fumigations
conducted
at
the
hydrogen
cyanide
fumigation
facility
were
used
to
assess
occupational
exposure
and
risk
from
citrus
fumigation.
Dermal
exposures
are
not
expected
based
on
the
limited
use
pattern
and
were
therefore
not
assessed.
Worker
exposure
and
risk
estimates
indicate
that
occupational
exposures
are
below
HED's
level
of
concern.

Use
of
Human
Studies
This
risk
assessment
relies
in
part
on
data
from
studies
in
which
adult
human
subjects
were
intentionally
exposed
to
a
pesticide
or
other
chemical.
These
studies,
listed
below,
have
been
determined
to
require
a
review
of
their
ethical
conduct.
They
are
also
subject
to
review
by
the
Human
Studies
Review
Board
(
HSRB).
All
of
the
listed
studies
have
received
the
appropriate
review
by
the
HSRB
and
have
been
determined
to
be
ethically
and
scientifically
acceptable.

Moertel,
CG
et
al
(
1982)
A
Clinical
Trial
of
Amygdalin
(
Laetrile)
in
the
Treatment
of
Human
Cancer.
New
England
Journal
of
Medicine,
Vol.
306,
No.
4:
201­
206
(
MRID
46769602).

Moertel,
CG
et
al
(
1981)
A
Pharmacologic
and
Toxicological
Study
of
Amygdalin.
JAMA,
Vol.
245,
No.
6:
591­
594
(
MRID
46769601)

2.0
INGREDIENT
PROFILE
2.1
Summary
of
Registered
and
Proposed
Uses
There
are
eight
active
registrations
for
sodium
cyanide
and
one
SLN
according
to
the
Office
of
Pesticide
Programs
Information
Network
(
OPPIN).
Table
1
provides
summary
information
on
registered
products
and
uses.

Table
1.
Active
Label
Registrations
for
Sodium
Cyanide
Reg
#
Name
Formulation
Government
Entity/
Company
%
ai
13808­
8
M­
44
Cyanide
Capsules
Capsule
South
Dakota
Dept
of
Agriculture
91.06
33858­
2
M­
44
Cyanide
Capsules
Capsule
Texas
Department
of
Agriculture
91.06
35975­
2
M­
44
Cyanide
Capsules
Capsule
Montana
Department
of
Livestock
91.06
35978­
1
M­
44
Cyanide
Capsules
Capsule
Wyoming
Dept
of
Agriculture
91.06
39260­
1
M­
44
Cyanide
Capsules
Capsule
Navajo
Fish
&
Wildlife
Department
91.06
39508­
1
M­
44
Cyanide
Capsules
Capsule
New
Mexico
Department
of
Agriculture
91.06
56228­
15
M­
44
Cyanide
Capsules
Capsule
U.
S.
Department
of
Agriculture
91.06
56228­
32
M­
44
Cyanide
Capsules
Capsule
U.
S.
Department
of
Agriculture
91.06
CA840006
Sodium
Cyanide
Powder
Washburn
&
Sons
98
Page
9
of
44
2.2
Structure,
Nomenclature,
and
Physical/
Chemical
Properties
The
nomenclature
and
physicochemical
properties
of
hydrogen
cyanide
are
provided
in
Tables
2
and
3.

TABLE
2.
Test
Compound
Nomenclature
Compound
Sodium
Cyanide
Hydrogen
Cyanide
Chemical
Structure
NaCN
HC=
N
Common
Name
sodium
cyanide
hydrogen
cyanide
Synonyms
Hydrocyanic
acid,
prussic
acid,
formonitrile,
formic
anammonide,
carbon
hydride
nitride,
cyclon
cyanobrik,
cyanogran,
sodium
cyanide,
hydrocyanic
acid
sodium
salt,
cymag
CAS
#
74­
90­
8
143­
33­
9
PC
Code
045801
074002
Current
Food/
Feed
Site
Registration
Citrus
Citrus
Source:
OSHA,
2004
TABLE
3.
Physicochemical
Properties
of
the
Technical
Grade
Test
Compound
Parameter
Sodium
Cyanide
Hydrogen
Cyanide
Molecular
Weight
49.01
27.03
Boiling
Point
1496
C
at
760
mm
Hg
26
C
at
760
mm
Hg
Melting
Point
564
C
­
13.4
C
Specific
Gravity
1.7
0.7
at
20
C
Vapor
Density
­­
0.94
Vapor
Pressure
Negligible
620
mm
Hg
at
20C
Solubility
Soluble
in
water
(
37
g/
100mL)
Miscible
with
water
and
alcohol,
slightly
soluble
in
ether.

pKa
­­
9.22
Source:
OSHA,
2004
3.0
METABOLISM
ASSESSMENT
3.1
Comparative
Metabolic
Profile
3.1.1
Metabolism
in
Mammals
Cyanide
gas
and
salts
such
as
sodium
and
potassium
cyanide
are
rapidly
absorbed
following
inhalation
and
oral
exposure,
but
are
more
slowly
absorbed
by
dermal
exposure.
Following
inhalation,
cyanide
is
rapidly
distributed
throughout
the
body,
with
measurable
levels
detected
in
all
organs.
Cyanide
can
be
distributed
in
the
body
within
seconds
and
death
can
occur
within
minutes.
Animal
studies
have
shown
that
cyanide
per
se
does
not
accumulate
in
the
blood
and
tissues
following
chronic
oral
exposure,
however.
This
is
due
to
the
fact
that
cyanide
is
transformed
to
the
much
less
toxic
thiocyanate
in
the
body,
with
a
plasma
half­
life
of
20
minutes
to
1
hour.
Hydrogen
cyanide
is
readily
converted
to
thiocyanate
in
the
liver
by
the
enzyme
rhodanese
and
this
metabolic
conversion
is
the
major
detoxification
mechanism
for
hydrogen
Page
10
of
44
cyanide.
Once
thiocyanate
is
formed,
it
is
not
converted
back
to
cyanide.
Cyanide
metabolites
are
mainly
excreted
in
the
urine,
with
small
amounts
excreted
through
the
lungs.

3.1.2
Plant
Metabolism
The
nature
of
the
residue
in
citrus
is
adequately
defined.
The
residue
of
concern
is
hydrogen
cyanide
per
se.
Hydrogen
cyanide
is
rapidly
absorbed
by
fresh
citrus,
and
depending
upon
conditions,
between
70
to
95%
of
available
hydrogen
cyanide
is
absorbed
within
one
hour.
Upon
aeration,
less
than
5
percent
of
the
sorbed
hydrogen
cyanide
is
desorbed.
After
48
hours,
most
of
the
sorbed
hydrogen
cyanide
is
"
irreversibly
bound."
There
is
no
evidence
that
any
of
the
sorbed
hydrogen
cyanide
is
degraded;
hydrogen
cyanide
is
stable
under
acidic
conditions.
The
available
data
show
that
over
90%
of
the
hydrogen
cyanide
can
be
accounted
for
as
such
in
the
treated
citrus
or
as
unsorbed
hydrogen
cyanide.
A
study
subsequently
obtained
from
University
of
California,
Riverside
indicates
that
when
citrus
is
fortified
with
hydrogen
cyanide
about
10%
of
the
hydrogen
cyanide
is
unrecoverable.
The
studies
and
data,
which
the
petition
response
cites,
were
not
available,
however,
to
verify
these
claims
(
PP#
1E1124;
2/
17/
71;
W.
Cox).

3.1.3
Livestock
Metabolism
The
nature
of
the
residue
in
livestock
has
not
been
defined.
However,
there
is
limited
potential
for
exposure
to
livestock
though
feed
items
because
citrus
treated
with
hydrogen
cyanide
is
destined
for
fresh
market
only.
(
Personal
communication,
Bill
Chism,
BEAD).
Additionally,
the
Agency
response
to
PP#
1E1124
indicates
that
hydrogen
cyanide,
when
ingested
by
animals
at
subtoxic
levels,
is
rapidly
detoxified
into
carbon
dioxide
and
thiocyanate,
which
is
largely
excreted
by
the
kidneys
(
2/
17/
71;
W.
Cox).

3.2
Environmental
Degradation
Sodium
cyanide
hydrolyzes
readily
to
gaseous
hydrogen
cyanide
when
dissolved
in
water
or
in
contact
with
moisture.
This
reaction
is
the
primary
reaction
in
the
environment.
EFED
does
not
anticipate
significant
exposure
from
sodium
cyanide
or
hydrogen
cyanide
in
surface
water
and
ground
water,
when
it
is
used
as
a
fumigant
under
controlled
delivery
system
of
gaseous
hydrogen
cyanide
into
an
airtight
enclosure
as
described
in
the
sodium
cyanide
label
(
SLA
CA
840006).
Residual
hydrogen
cyanide
will
be
vented
from
the
treated
containers
through
a
exhaust
system.
In
a
recent
air
monitoring
study
(
MRID
#
46648901),
eight­
hour
time­
weighted
average
concentration
of
hydrogen
cyanide
in
ambient
air
after
fumigation
of
citrus
truck
trailers
was
zero
ppm.
Based
on
the
nature
of
the
fumigation
operation,
and
due
to
the
high
vapor
pressure
(
620
mm
Hg
at
20C)
and
Henry's
Law
Constant
(
1.33
x
10­
4
atm­
m3/
mole)
of
hydrogen
cyanide,
redeposition
of
volatilized
hydrogen
cyanide
in
surface
water
does
not
appear
to
be
significant,
thus
suggesting
that
contamination
of
surface
waters
and
ground
water
by
hydrogen
cyanide
is
unlikely.
Page
11
of
44
3.3
Metabolites
and
Degradates
A
summary
of
hydrogen
cyanide
parent
and
metabolite
matrices
is
provided
in
Table
4.

Table
4.
Tabular
Summary
of
Metabolites
and
Degradates
Chemical
Name
Commodity
Matrices­
Major
Residue
(>
10%
TRR)
Matrices­
Minor
Residue
(<
10%
TRR)
Chemical
Structure
Citrus
90%
NA
Ruminants
NA
NA
Hydrogen
Cyanide
Poultry
NA
NA
HC=
N
3.4
Summary
of
Residues
for
Tolerance
Expression
and
Risk
Assessment
A
summary
of
metabolites
and
degradates
included
in
the
risk
assessment
and
tolerance
expression
is
provided
in
Table
5.
The
Agency
concluded
in
the
response
to
petition
PP#
1E1124
that
feed
uses
of
treated
citrus
are
of
little
concern
because
the
proposed
use
is
for
fruit
destined
for
the
fresh
market
only.
Therefore
livestock
commodities
were
not
included
in
the
dietary
risk
assessment
and
tolerances
for
ruminant
and
poultry
commodities
are
not
required.
Based
on
available
data,
the
established
tolerance
for
this
commodity
is
adequate
(
Table
6).
Codex
maximum
residue
limits
(
MRLs)
do
not
currently
exist
for
hydrogen
cyanide;
therefore,
no
questions
of
compatibility
with
U.
S.
tolerances
exist.

Table
5.
Metabolites
and
Degradates
to
be
included
in
the
Risk
Assessment
and
Tolerance
Expression
Matrix
Residues
included
in
Risk
Assessment
Residues
included
in
Tolerance
Expression
Plant
Citrus
Hydrogen
Cyanide
Hydrogen
Cyanide
Ruminant
NA
NA
Livestock
Poultry
NA
NA
Drinking
Water
NA
NA
Table
6.
Tolerance
Summary
for
Hydrogen
Cyanide
Commodity
Established
Tolerance
(
ppm)
Recommended
Tolerance
(
ppm)
Comments
(
correct
commodity
definition)
Fruit,
citrus
50
50
Fruit,
citrus,
group
10
4.0
HAZARD
CHARACTERIZATION/
ASSESSMENT
4.1
Hazard
Characterization
The
toxicology
database
for
hydrogen
cyanide
is
incomplete.
No
guideline
studies
are
available.
All
of
the
critical
studies
are
cited
from
the
open
literature.
Data
on
all
forms
of
cyanide
(
e.
g.,
hydrogen,
sodium,
potassium
cyanide
etc.)
have
been
used
to
identify
hydrogen
cyanide
toxicity
for
this
assessment.
Hydrogen
cyanide
is
extremely
acutely
toxic
by
all
exposure
routes.
Page
12
of
44
All
forms
of
cyanide,
hydrogen,
sodium,
and
potassium,
are
extremely
acutely
toxic
by
the
oral
route.
Based
on
an
analysis
of
case
history
data
the
lowest
fatal
oral
dose
of
hydrogen
cyanide
for
an
average
adult
human
is
estimated
by
FDA
to
be
1
mg/
kg
(
FDA,
1956).
The
lowest
reported
fatal
dose
of
cyanide
(
unspecified
form)
in
humans
was
estimated
to
be
0.56
mg/
kg
based
on
incidence
data
published
in
1938
(
Gettler
and
Baine,
1938).
It
is
important
to
note
that
analytical
measurements
at
the
time
these
studies
were
conducted
lack
the
precision
of
current
technology.
Both
sodium
and
potassium
cyanide
have
lethal
doses
of
200
mg
total,
representing
81
and
110
mg
total
hydrogen
cyanide,
respectively.
The
acute
oral
fatal
dose
of
potassium
cyanide
in
rats
is
10­
15
mg/
kg,
which
is
equivalent
to
a
4­
6
mg/
kg
hydrogen
cyanide.

Results
of
clinical
trials
of
Laetrile
to
treat
cancer
also
provide
evidence
of
the
acute
oral
toxicity
of
hydrogen
cyanide.
Laetrile,
also
known
as
amygdalin,
is
a
plant
compound
that
produces
cyanide.
Use
of
Laetrile
has
been
shown
to
produce
side
effects
of
cyanide
poisoning 
which
can
produce
a
range
of
symptoms,
including
death.
In
a
clinical
trial
of
Laetrile
to
treat
human
cancer,
the
single
dose
of
0.5
g
of
amygdalin
was
determined
to
be
minimally
toxic;
a
single
dose
of
0.5
g
of
amygdalin
is
equivalent
to
0.4
mg/
kg
hydrogen
cyanide/
day
(
Moertel
et
al,
1982).
Blood
levels
of
cyanide
rose
when
the
single
0.5
g
dose
was
doubled
to
two
0.5
g
doses
at
an
administration.
These
increased
blood
levels
were
associated
with
an
increase
in
the
incidence
and
severity
of
some
of
the
toxic
signs
and
symptoms
due
to
the
release
of
hydrogen
cyanide
from
amygdalin
by
the
enzymatic
action
of
B­
glucosidase,
an
intestinal
enzyme.
Therefore,
the
single
dose
of
0.5
g
of
amygdalin
was
determined
to
be
a
minimally
toxic
dose,
whereas
the
double
dose
was
generally
regarded
as
frankly
toxic.

Hydrogen
cyanide
is
also
acutely
toxic
via
inhalation.
The
dose­
effect
curve
of
the
acute
inhalation
effects
in
humans
is
steep.
Whereas
slight
effects
occur
at
exposure
to
hydrogen
cyanide
levels
of
20­
40
mg/
m3,
50­
60
mg/
m3
can
be
tolerated
without
immediate
or
late
effects
for
20
minutes
to
1
hour,
120­
150
mg/
m3
is
dangerous
to
life
and
may
lead
to
death
after
0.5­
1
hour,
150
mg/
m3
is
likely
to
be
fatal
within
30
minutes,
200
mg/
m3
is
likely
to
be
fatal
after
10
minutes,
and
300
mg/
m3
is
immediately
fatal.
It
should
be
emphasized
that
this
represents
crude
average
exposure
estimates,
based
on
various
studies
(
WHO,
2004).

An
average
LD50
value
for
dermal
exposure
of
100
mg/
kg
was
estimated
for
humans
(
Rieders,
1971).
Concentrations
of
7000­
12,000
mg/
m3
were
estimated
to
be
fatal
after
a
5
minute
exposure
of
workers
with
self­
contained
respirators
without
effective
skin
protection
(
Minkina,
1988).
Cyanides
are
weakly
irritating
to
the
skin
and
eye.
No
data
are
available
on
sensitizing
properties.

The
primary
effects
of
acute
cyanide
exposure
in
humans
are
central
nervous
system
and
cardiovascular
disturbances.
Typical
signs
of
acute
cyanide
poisoning
include
tachypnea,
headache,
vertigo,
lack
of
motor
coordination,
weak
pulse,
cardiac
arrhythmias,
vomiting,
stupor,
convulsions,
and
coma.
Page
13
of
44
Hydrogen
cyanide
exhibits
relatively
low
subchronic
and
chronic
toxicity
by
the
oral
route.
A
2­
year
rat
feeding
study
(
Howard
and
Hanzal,
1955)
with
hydrogen
cyanide
fumigated
food
containing
residues
up
to
300
ppm
(
10.8
mg/
kg/
day)
showed
no
treatment­
related
effects
in
clinical
signs,
body
weight,
food
consumption,
hematology,
gross
necropsy
or
histopathological
changes
in
the
organs
examined
(
heart,
lung,
liver,
spleen,
gastrointestinal
tract,
kidneys,
adrenal,
thyroid,
testes,
uterus,
ovaries,
cerebrum,
cerebellum,
and
brain).
The
rats
in
the
2­
year
study
ingested
2
to
3
times
the
fatal
acute
dose
of
hydrogen
cyanide
in
rats
each
day
throughout
their
lifetime
without
any
measurable
effects.
In
a
13
week
repeated
dose
toxicity
study
in
which
sodium
cyanide
was
administered
in
the
drinking
water,
there
were
no
mortalities,
clinical
signs
or
histopathological
effects
in
the
brain,
thyroid,
or
other
organs
of
rats
and
mice
exposed
to
doses
up
to
12.5
and
26
mg/
kg/
day
respectively.

Hydrogen
cyanide
is
readily
converted
to
thiocyanate
in
the
liver
by
the
enzyme
rhodanese.
This
metabolic
conversion
is
the
major
detoxification
mechanism
for
hydrogen
cyanide.
The
conversion
of
cyanide
to
thiocyanate
was
first
demonstrated
in
1894.
Conversion
of
cyanide
to
thiocyanate
is
enhanced
when
cyanide
poisoning
is
treated
by
intravenous
administration
of
a
sulfur
donor
(
e.
g.,
sodium
thiosulfate).
Definite
increases
in
thiocyanate
concentrations
were
found
in
the
treated
tissues
of
the
experimental
animals
indicating
that
metabolic
detoxification
of
hydrogen
cyanide
had
occurred
(
Howard
and
Hanzal,
1956).
Residues
of
thiocyanate,
the
less
toxic
primary
metabolite
of
cyanide,
increased
3.5­
fold
in
plasma,
3.5
fold
in
erythrocytes,
1.3
fold
in
liver,
and
2.5fold
in
kidneys
of
the
rats
exposed
to
hydrogen
cyanide
in
the
diet.
The
rapidity
of
this
conversion
was
demonstrated
in
a
case
of
humans
where
one­
twentieth
the
lethal
dose
(
0.1­
0.2
mg/
kg
BW)
of
soluble
cyanide
was
injected
intravenously
every
ten
minutes.
In
this
case,
more
than
the
equivalent
of
an
acutely
fatal
dose
was
administered
without
any
apparent
harm
to
the
individual
(
FDA,
1956).
Based
on
the
FDA
study,
as
long
as
the
oral
intake
of
hydrogen
cyanide
does
not
exceed
the
body's
detoxification
mechanisms
via
the
formation
of
thiocyanate,
hydrogen
cyanide
can
be
ingested
in
the
form
of
dietary
residues
for
prolonged
periods
without
harm.
Once
thiocyanate
is
formed,
it
is
not
converted
back
to
cyanide.
It
has
been
estimated
that
based
on
established
tolerances
and
percentage
in
the
daily
diet,
the
TMRC
for
the
total
daily
diet
could
represent
about
14
ppm
hydrogen
cyanide
(
FDA,
1956).

Cyanogenic
glycosides
are
present
in
major
edible
plants
(
WHO,
2004).
Amygdalin
occurs
in
almonds,
dhurrin
in
sorghum,
linamarin
in
cassava,
lotaustralin
in
cassava
and
lima
beans,
prunasin
in
stone
fruit,
and
taxiphyllin
in
bamboo
shoots
(
WHO,
2004).
Cassava
is
an
important
subsistence
crop
for
450­
500
million
people
in
26
tropical
countries
in
the
expanding
populations
of
Africa
and
South
America.
World
production
in
1980
was
estimated
to
be
118
million
tons.
Cassava
has
been
suspected
as
a
cause
of
human
congenital
defects
(
ATSDR,
2004).

There
are
neurotoxicity,
developmental
and
reproductive
studies
available
with
naturally
occurring
cyanides
or
cyanide
salts
in
the
open
literature,
but
there
are
no
EPA
guideline
studies
of
these
types
of
studies
in
the
available
database.
Neurotoxic
effects
are
a
major
occurrence
across
species
and
in
humans
from
exposure
to
cyanide
in
its
various
forms.
In
several
animal
Page
14
of
44
studies,
developmental
CNS
and
heart
malformations
occur
in
the
presence
of
overt
maternal
toxicity
(
including
death),
whereas,
parental
findings
(
mortality)
occur
at
slightly
higher
doses
in
the
absence
of
reported
reproductive
results
in
inhalation
studies
with
acetone
cyanohydrin
(
ACH)
in
rats.
ACH
rapidly
converts
to
hydrogen
cyanide
at
physiological
pH.
The
effects
of
acute
cyanide
exposure
in
humans
are
dominated
by
CNS
and
cardiovascular
disturbances
(
ATSDR,
2004).
Typical
signs
of
acute
cyanide
poisoning
include
tachypnea,
headache,
vertigo,
lack
of
motor
coordination,
weak
pulse,
cardiac
arrhythmias,
vomiting,
stupor,
convulsions,
and
coma.
No
additive
or
synergistic
effect
was
observed
in
the
fatalities
between
cyanide
and
other
factors,
such
as
carbon
monoxide,
alcohol,
age
of
victims,
and
presence
of
heart
disease
(
WHO,
2004)

There
are
no
guideline
studies
of
carcinogenicity
of
hydrogen
cyanide
or
its
alkali
salts.
There
are
no
available
open
literature
studies
on
the
carcinogenic
potential
of
cyanide.
The
classification
of
the
carcinogenic
potential
could
not
be
determined
due
to
the
absence
of
acceptable
cancer
studies
in
rats
and
mice.
Because
of
cyanide's
high
toxicity,
it
would
be
difficult
to
conduct
a
meaningful
cancer
study
in
rats
and
mice
over
a
two­
year
period.
Hydrogen
cyanide
has
been
evaluated
for
mutagenic
potential
with
mixed
results
and
several
open
literature
references
are
available.

Cyanide
gas
and
salts
such
as
sodium
and
potassium
cyanide
are
rapidly
absorbed
following
inhalation
and
oral
exposure.
Cyanide
compounds
are
more
slowly
absorbed
by
dermal
exposure.
Cyanide
can
be
distributed
in
the
body
within
seconds
and
death
can
occur
within
minutes.
Following
oral
exposure,
the
highest
levels
have
been
detected
in
lungs
and
blood.
Following
inhalation,
cyanide
is
rapidly
distributed
throughout
the
body,
with
measurable
levels
detected
in
all
organs.
Animal
studies
have
shown
that
cyanide
does
not
accumulate
in
the
blood
and
tissues
following
chronic
oral
exposure.
Cyanide
is
transformed
to
the
much
less
toxic
thiocyanate
in
the
body,
with
a
plasma
half­
life
of
20
minutes
to
1
hour.
Cyanide
metabolites
are
mainly
excreted
in
the
urine,
with
small
amounts
excreted
through
the
lungs
(
ATSDR,
2004).

Hydrogen
cyanide
does
not
react
with
bivalent
iron
of
hemoglobin
(
Fe++).
It
does
however,
bind
with
cytochrome
oxidase
(
a
ferric
enzyme)
in
the
electron
transport
system
and
inhibits
the
exchange
of
oxygen
from
the
blood
to
the
tissues
by
the
mechanism
of
competitive
inhibition.
Cyanide
can
also
inhibit
approximately
40
enzymes,
including
a
number
of
other
metalloenzymes
containing,
for
the
most
part,
iron,
copper,
or
molybdenum
(
e.
g,
alkaline
phosphatase,
carbonic
anhydrase,
catalase,
peroxidase,
ascorbic
acid
oxidase,
xanthine
oxidase,
and
succinic
dehydrogenase).
These
reactions
may
also
contribute
to
cyanide
toxicity
(
WHO,
2004).
Due
to
its
high
dependency
on
oxidative
metabolism
and
limited
anaerobic
capacity,
the
central
nervous
system
is
particularly
vulnerable
to
cyanide
intoxication.
The
CNS
symptoms
observed
in
cyanide
toxicity
parallel
those
observed
following
accumulation
of
calcium
in
the
brain
and
cytosolic
calcium
ion
overload
has
been
implicated
as
an
intracellular
mediator
of
cellular
injury
during
and
after
anoxic
hypoxia
(
WHO,
2004).

Tables
7
and
8
provide
the
toxicity
profile
for
hydrogen
cyanide.
Page
15
of
44
Table
7.
Acute
Toxicity
Profile
­
Hydrogen
Cyanide
Guideline
No.
Study
Type
MRID(
s)
Results
Toxicity
Category
870.1100
Acute
oral
[
rat]
Potassium
Cyanide
expressed
as
equivalents
of
hydrogen
cyanide
N/
A*
LD50
=
4­
6
mg/
kg
I
*
Handbook
of
Toxicology,
(
1956),
Vol.
1,
Ed.
William
S.
Spector,
p.
242,
Toxicity
of
Potassium
Cyanide;
W.
B.
Saunders
Co.,
Philadelphia
and
London.

Table
8.
Subchronic,
Chronic
and
Other
Toxicity
Profile
­
Hydrogen
Cyanide
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3100
90­
Day
oral
toxicity
(
rats,
mice)
(
NTP,
1993)
Acceptable/
Non­
guideline
0,
0.2,
0.5,
1.4,
4.5,
12.5
mg
NaCN/
kg/
day
(
M)
and
0,
0.2,
1.7,
4.9,
12.5
mg
NaCN/
kg/
day
(
F)
in
rats
in
drinking
water
and
0,
0.3,
1,
3,
9,
and
26
mg
NaCN/
kg/
day
in
mice
in
drinking
water
NOAEL
=
2.5
mg/
HCNkg/
day
LOAEL
=
8.9
mg/
HCNkg/
day
based
on
slight
changes
in
the
reproductive
tract
in
male
rats.
No
adverse
effects
in
female
rats
or
mice.

870.3465
4­
Week
inhalation
toxicity
(
rat)
Monsanto
Co.
(
1985),
Acceptable/
Nonguideline
Dose:
207
mg
acetone
cyanohydrin
(
ACH)/
m3
calculated
as
71
mg
HCN/
m3.
NOAEL
=
not
established
LOAEL
=
71
mg
HCN/
m3
produced
30%
mortality
(
3/
10)
among
rats
exposed
part
of
one
day.

870.3465
14­
week
dietary
toxicity
study
(
dogs)
Kamalu
(
1993)
Unacceptable/
Non­
guideline,
Doses:
(
1)
control
(
zero
mg
HCN/
kg
rice
diet),
(
2)
cassava
["
gari"]
(
believed
to
liberate
10.8
mg
HCN/
kg
cassava
diet),
(
3)
rice
+
added
NaCN
(
10.8
mg
NaCN
added/
kg
rice
diet)
10.8
mg
HCN/
kg
diet
calculated
as
1.08
mg
HCN/
kg
BW
NOAEL
=
not
established
LOAEL
=
1.08
mg
HCN/
kg
BW
(
NaCN
+
rice)
based
on
altered
profile
of
free
amino
acids,
but
no
effects
on
histology
of
liver,
kidney
or
heart,
although
serum
enzymes
(
plasma
glutamyl
transferase,
ALAT,
isocitrate
dehydrogenase)
were
altered.
Adrenal
hyperplasia
and
hypertrophy,
and
pancreatic
nephrosis
and
fibrosis
were
observed
with
rice
+
NaCN.
Additionally,
a
significantly
reduced
frequency
of
testicular
tubules
in
Stage
8
of
sperm
cycle
as
well
as
marked
germ
sloughing
off
and
testicular
degeneration
was
also
seen
in
the
rice
+
NaCN
test
animals
(
6
dogs/
group).
Thiocyanate
levels
in
NaCN
+
rice
treated
dogs
increased
during
the
study.
In
contrast,
results
of
the
"
gari"
diet
(
cassava)
showed
generalized
congestion
and
hemorrhage,
liver
vacuolation,
kidney
vacuolation,
myocardial
degeneration,
adrenal
gland
degeneration,
pancreatic
necrosis,
decreased
T3
and
thyroid
effects
consistent
with
goiter.
870.3465
90­
Day
inhalation
toxicity
(
rat)
Monsanto
Co.
(
1984a),
Acceptable/
Non­
guideline,
Doses
0,
36,
101,
204
mg/
m3
acetone
cyanohydrin
(
ACH)
calculated
as
0,
11,
32,
65
mg
HCN/
m3
NOAEL
=
65
mg
HCN/
m3
or
15
mg
HCN/
kg/
day
LOAEL
=
not
established.

870.3465
6­
Month
inhalation
toxicity
(
monkey,
rat)
Lewis
et
al
(
1984)
Acceptable/
Nonguideline
Doses
0,
11
ppm,
25
ppm
cyanogen
calculated
as
25,
or
56
mg
HCN/
m3.
NOAEL
=
25
ppm
HCN
LOAEL
=
56
ppm
HCN
based
on
doubling
of
the
rate
of
responding
on
a
variable
interval
2.9
min
schedule
of
reinforcements
and
decreased
lung
moisture
content
in
monkeys
and
decreased
body
weights
in
rats.
870.3700a
Prenatal
Doherty
et
al
(
1982)
Acceptable/
Nonguideline
Maternal
NOAEL
=
0.07
mmol/
kg
HCN
BW/
hour
Maternal
LOAEL
=
0.073
mmol/
kg
HCN
BW/
hr
Page
16
of
44
Table
8.
Subchronic,
Chronic
and
Other
Toxicity
Profile
­
Hydrogen
Cyanide
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
developmental
in
(
golden
hamster)
Doses
0,
0.125,
0.133
mmol
NaCN/
kg
BW/
hour
using
osmotic
minipumps
(
preliminary
study)
given
on
days
6­
9
of
gestation
based
on
maternal
deaths
and
dyspnea,
incoordination,
reduced
body
temperature,
and
loss
of
body
weight
Developmental
NOAEL
=
0.07
mmol/
kg
HCN
BW/
hour
Developmental
LOAEL
=
0.073
mmol/
kg
HCN
BW/
hr
based
on
100%
resorptions
870.3700a
Prenatal
developmental
in
(
golden
hamster)
Doherty
et
al
(
1982)
Acceptable/
Nonguideline
Doses:
0,
0.126,
0.1275,
or
0.1295
mmol
NaCN/
kg
BW/
hour
using
osmotic
minipumps
equivalent
to
0,
78.7,
79.6,
and
80.9
mg
NaCN/
kg
BW/
day
given
on
days
6­
9
of
gestation
Maternal
NOAEL
=
not
established
Maternal
LOAEL
=
0.126
mmol
NaCN/
kg
BW/
hr
based
on
salivation,
shortness
of
breath,
ataxia,
reduced
body
temperature,
and
loss
of
body
weight
Developmental
NOAEL
=
not
established
Developmental
LOAEL
=
0.126
mmol
NaCN/
kg
BW/
hr
based
on
resorptions,
non­
closure
of
neural
tube,
exencephaly,
encephalocoele,
and
malformations
of
the
heart,
limb,
or
tail.
Co­
administration
of
thiosulfate
eliminated
the
teratogenic
effect,
protecting
the
dams
and
fetuses
from
the
toxic
effects
of
cyanide
870.3700a
Prenatal
developmental
in
(
rats)
Monsanto
Co.
(
1982,
1983a)
Acceptable/
Guideline
Doses:
0,
1,
3,
10
mg
Acetone
cyanohydrin/
kg
BW
(
equivalent
to
0,
0.3,
0.9,
or
3
mg
cyanide/
kg
BW/
day)
during
days
6­
15
of
gestation
Maternal
NOAEL
=
0.3
mg
HCN/
kg
BW/
day
Maternal
LOAEL
=
0.9
mg
HCN/
kg
BW/
day
based
on
slight
reductions
in
weight
gain
and
significant
decreases
in
high
dose
group
plus
decrease
in
implantations
Developmental
NOAEL
=
3
mg
HCN/
kg
BW/
day
Developmental
LOAEL
=
not
established
870.3700a
Prenatal
developmental
in
(
rats)
Singh
(
1981)
Unacceptable/
Nonguideline
Doses:
50%
and
80%
milled
cassava
powder
in
diet
given
during
first
15
days
of
gestation
(
CN
content
not
specified)
Maternal
LOAEL
=
50%
milled
cassava
resulted
in
decreased
weight
gain
Developmental
LOAEL
=
50%
milled
cassava
resulted
in
increased
resorptions,
decreased
body
weight,
and
open
eye,
microcephaly,
limb
defects
at
80%
milled
cassava
870.3700a
Prenatal
developmental
in
(
golden
hamster)
Willhite
(
1982)
Unacceptable/
Nonguideline
Doses
of
200,
250,
or
275
mg/
kg
BW
of
d/
l­
amygdalin
or
177
mg/
kg
BW
of
d­
prunasin
equivalent
to
11,
14,
or
16
mg
CN/
kg
BW,
respectively,
or
16
mg
CN/
kg
BW
administered
orally
on
day
8
of
gestation
or
16
mg
CN/
kg
BW/
day
given
intravenously
Maternal
oral
LOAEL
=
11
mg
HCN/
kg
BW
/
day,
effects
not
specified.
Developmental
oral
LOAEL
=
11
mg
HCN/
kg
BW/
day
based
on
exencephaly,
encephalocoele,
skeletal
malformations
No
developmental
effects
were
seen
at
16
mg
HCN/
kg
BW/
day
given
intravenously
870.3700a
Prenatal
developmental
in
(
golden
hamster)
Frakes
et
al
(
1985)
Acceptable/
Nonguideline
Doses:
0,
70,
100,
120,
or
140
mg
linamarin/
kg
BW/
day
on
day
8
of
gestation
(
primitive
streak)
Maternal
NOAEL
=
70
mg
linamarin/
kg/
day
LOAEL
=
100
mg/
kg/
day
based
on
dyspnea,
tremors,
and
ataxia,
Developmental
NOAEL
=
100
mg
linamarin
/
kg/
day
LOAEL
=
120
mg
linamarin
/
kg/
day
based
on
vertebral
and
rib
anomalies
and
Encephalocoele.
870.3700a
Prenatal
developmental
in
(
golden
hamsters)
Frakes
et
al
(
1986)
Unacceptable/
Nonguideline
Doses
of
high
cyanide
(
bitter
cassava,
7.9
mmol
CN/
kg))
and
low
cyanide
(
sweet
cassava,
0.7
mmol
CN/
kg))
mixed
in
an
20:
80
ratio
given
on
days
3­
14
of
gestation
to
pregnant
hamsters
Maternal
LOAEL
=
based
on
significant
decreases
in
weight
gain.
Developmental
LOAEL
=
based
on
decreased
fetal
body
weight,
reduced
ossification
of
sacrocaudal
vertebrae,
metatarsals,
and
sternebrae.
Page
17
of
44
Table
8.
Subchronic,
Chronic
and
Other
Toxicity
Profile
­
Hydrogen
Cyanide
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
870.3800
Reproduction
and
fertility
effects
(
rat)
Olusi
et
al
(
1979)
Acceptable/
Nonguideline
Doses
of
1000
or
2000
mg
CN/
kg
BW/
day
administered
to
females
(
10/
sex)
for
2­
weeks
and
then
mated
to
untreated
males
Parental/
Systemic
NOAEL
=
not
established
LOAEL
=
1000
mg
HCN
/
kg/
day
based
on
decreased
weight
gain,
blood
hemoglobin,
serum
T4
concentration.
Reproductive
NOAEL
=
not
established
LOAEL
=
1000
mg
HCN/
kg/
day
based
on
no
pregnancies.
870.3800
Reproduction
and
fertility
effects
(
male
rat)
Monsanto
Co.
(
1985a)
Acceptable/
Non­
guideline,
Inhalation
doses
of
0,
35,
101,
or
202
mg
acetone
cyanohydrin
(
ACH)/
m3
equivalent
to
0,
11,
32,
or
64
mg
HCN/
m3
for
6
hours/
day,
5
days/
week
during
a
period
of
69
days
(
48
exposure
days).
Following
exposure,
the
males
were
mated
with
3
untreated
females/
male
Parental/
Systemic
NOAEL
=
64
mg
HCN/
m3
based
on
no
deaths,
clinical
signs
of
toxicity
LOAEL
=
not
established.
Reproductive
NOAEL
=
64
mg
HCN/
m3
based
on
mating
efficiency,
number
of
live
implants,
and
pre­
and
post­
implantation
loss
LOAEL
=
not
established.
Offspring
NOAEL
=
not
established
LOAEL
=
not
established.

870.3800
Reproduction
and
fertility
effects
(
rat)
Monsanto
Co.
(
1985b)
Acceptable/
Non­
guideline,
Inhalation
doses
of
0,
38,
108,
or
207
mg
acetone
cyanohydrin
(
ACH)/
m3
equivalent
to
0,
12,
34,
or
66
mg
HCN/
m3
for
6
hours/
day,
7
days/
week
up
to
day
of
mating
(
34­
36
exposures).
Following
exposure,
the
females
were
mated
with
untreated
males;
females
were
sacrificed
at
gestation
days
13­
15.
Parental/
Systemic
NOAEL
=
66
mg
HCN/
m3
based
on
absence
of
clinical
signs,
except
for
red
nasal
discharge,
mortality,
weight
gain
and
necropsy,
LOAEL
=
not
established.
Reproductive
NOAEL
=
66
mg
HCN/
m3
based
on
no
effect
on
fertility,
LOAEL
=
not
established.
Offspring
NOAEL
=
not
established,
LOAEL
=
not
established.

870.3800
Reproduction
and
fertility
effects
(
rat)
Tewe
and
Maner
(
1981a)
Unacceptable/
Non­
guideline,
Doses:
0,
500
ppm
dietary
KCN
added
to
cassava
flour
fed
to
pregnant
female
rats
during
gestation
and
lactation
Parental/
Systemic
LOAEL
=
207
HCN
ppm
in
diet
based
on
decreased
body
weight
gain
during
lactation.
Reproductive
NOAEL
=
207
KCN
ppm
in
diet
did
not
cause
marked
effect
in
gestation
and
lactation
performance
Offspring
LOAEL
=
207
HCN
ppm
in
diet
based
on
decreased
food
consumption
and
body
weight
during
lactation.
870.3800
Reproduction
and
fertility
effects
(
Yorkshire
pigs)
Tewe
and
Maner
(
1981b)
Acceptable/
Non­
guideline
Doses:
0,
250,
500
ppm
KCN
added
to
fresh
cassava
diets
and
fed
to
maternal
animals
during
gestation
and
lactation
Parental/
Systemic
NOAEL
=
104
HCN
ppm
in
diet
LOAEL
=
500
ppm
in
diet
based
on
increased
thyroid
weight
and
thyroid
and
kidney
histopathology.
Reproductive
NOAEL
=
207
HCN
ppm
in
diet
did
not
affect
the
production
or
lactation
of
the
first
litter
of
offspring
and
did
not
affect
either
the
number
or
weight
of
110­
day
old
fetuses
LOAEL
not
established
Offspring
NOAEL
=
104
HCN
ppm
in
diet
LOAEL
=
207
HCN
ppm
in
diet
based
on
increased
fetal
serum
thiocyanate
levels,
increased
relative
fetal
spleen
and
heart
weight.
870.4100a
Chronic
toxicity
(
rat)
Howard
and
Hanzal,
1955,
Acceptable/
Non­
guideline,
Doses:
0,
100,
300
ppm
calculated
as
0,
4.3,
10.8
mg/
kg/
day
of
HCN
NOAEL
=
10.8
mg
HCN
/
kg/
day
(
HDT)
LOAEL
=
not
established.

870.6200a
Acute
Neurotoxicity
(
rats)
Fechter
et
al
(
2002),
Acceptable/
Nonguideline
Dose:
34
mg
HCN/
m3
for
3.5
hours
HCN
plus
noise
produced
impaired
auditory
function
by
producing
significant
oxidative
stress
in
the
cochlea.
HCN
alone
did
not
cause
significant
hearing
loss
or
hair
cell
loss.
870.6200b
Mathangi
&
Namasivayam
(
2000),
Reductions
of
memory
(
T­
maze
test),
along
with
reductions
in
the
Page
18
of
44
Table
8.
Subchronic,
Chronic
and
Other
Toxicity
Profile
­
Hydrogen
Cyanide
Guideline
No./
Study
Type
MRID
No.
(
year)/
Classification
/
Doses
Results
Subchronic
neurotoxicity
(
rats)
Acceptable/
Non­
guideline,
Dose:
2
mg
NaCN/
kg
given
intraperitoneally
followed
by
25
ip
doses
which
was
25%
of
LD50.
level
of
dopamine
and
5­
hydroxytryptamine
and
increases
in
norepinephrine
and
epinephrine
levels
in
the
hippocampus,
measured
after
a
month
of
treatment.

870.6200b
Subchronic
neurotoxicity
(
dogs)
Hertting
et
al
(
1960)
Unacceptable/
Nonguideline
Doses:
0,
0.5,
2,
1­
4
mg
NaCN
capsule/
kg/
day
for
13­
15
months
(
only
one
dog
at
each
dose
level)
NOAEL
=
not
established
LOAEL
=
0.27
mg
HCN/
kg/
day
based
on
degenerative
changes
in
the
ganglia
cells
of
CNS,
interpreted
to
be
caused
by
multiple
episodes
of
acute
cerebral
hypoxia.
870.6200b
Subchronic
neurotoxicity
(
miniature
pigs)
Jackson
(
1988)
Acceptable/
Nonguideline
Doses:
0,
0.4,
0.7,
1.2
KCN/
kg/
day
dosed
by
gavage
once
daily
for
24
weeks
NOAEL
=
not
established
LOAEL
=
0.5
mg
HCN/
kg/
day
based
on
dose
related
decreased
T3
and
T4
and
increased
fasting
blood
sugar
plus
decreased
exploration
and
aggression,
slower
eating,
more
frequent
drinking
and
shivering
consistent
with
decreased
thyroid
activity.
870.3100
Subchronic
oral
(
human)
FDA
(
1956)
Administration
of
NaCN
to
measure
thiocyanate
in
saliva
Oral
NOAEL
=
0.2
mg
HCN/
kg/
day
870.3100
Subchronic
oral
and
intravenous
(
human)
Moertel
et
al
(
1982),
MRIDs
46769601
46769602
A
clinical
trial
of
amygdalin
(
laetrile)
in
the
treatment
of
human
cancer
and
Moertel
et
al
(
1981)
A
pharmacological
and
toxicological
study
of
amygdalin
Oral
LOAEL
=
0.4
mg
HCN/
kg/
day
based
on
symptoms
and
clinical
signs
of
hydrogen
cyanide
toxicity
Mutagenicity
Test
System
Endpoint
Result
With
Activation
Result
Without
Activation
Reference
Form
S.
typhimurium
TA82,
TA102
Reverse
Mutation
­
Not
tested
DeFlora
et
al,
1984
KCN
S.
typhimurium
TA98,
TA100,
TA1535,
TA1537,
TA1538
Reverse
Mutation
­
­
DeFlora
1981
KCN
S.
typhimurium
TA98,
TA100
Reverse
Mutation
­
(+)
­
+
Kushi
et
al,
1983
HCN
S.
typhimurium
TA98,
TA100
Reverse
Mutation
­
­
Kubo
et
al,
2002
KCN
S.
typhimurium
TA97,
TA98,
TA100,
TA1535
Reverse
Mutation
­
­
NTP
1993
NaCN
E.
coli
WP67,
CM871,
WP2
DNA
Repair
Test
­
­
DeFlora
et
al,
1984
KCN
HeLa
cells
DNA
Synthesis
Inhibition
­
­
Painter
and
Howard,
1982
KCN
Human
A549
lung
carcinoma
cells
DNA
Breakage
+(
cyt)
Vock
et
al,
1998
KCN
Human
TK6
lymphoblastoma
cells
DNA
Breakage
+(
cyt)
Henderson
et
al,
1998
KCN
Rat
thymocytes
DNA
Breakage
+(
cyt)
Bhattachrya
et
al,
1997
KCN
Hamster
BHK­
21
cells
DNA
Breakage
+(
cyt)
Bhattachrya
et
al,
1997
KCN
Rat
hepatocytes
DNA
Breakage
+(
cyt)
Storer
et
al,
1996
KCN
Mitochondrial
fraction
from
brain
of
male
ddy
mice
Mitochondrial
DNA
Breakage
+
Yamamoto,
2002
KCN
­
=
negative
result,
+
=
positive
result,
(+)
=
weakly
positive
result,
+(
cyt)
=
DNA
breakage
associated
with
cytotoxicity;
DNA
=
deoxyribonucleic
acid,
HCN
=
hydrogen
cyanide,
KCN
=
potassium
cyanide,
NaCN
=
sodium
cyanide
Page
19
of
44
4.2
FQPA
Hazard
Considerations
4.2.1
Adequacy
of
the
Toxicity
Data
Base
The
toxicology
database
for
hydrogen
cyanide
is
not
complete.
No
guideline
studies
are
available.
All
of
the
critical
studies
are
cited
from
the
open
literature.
Data
on
all
forms
of
cyanide
(
e.
g.,
hydrogen,
sodium,
potassium
cyanide
etc)
have
been
used
to
identify
hydrogen
cyanide
toxicity
for
this
assessment.

4.2.2
Evidence
of
Neurotoxicity
There
is
a
concern
for
neurotoxicity
resulting
from
exposure
to
cyanide,
since
several
of
the
reviewed
literature
studies
show
signs
of
neurotoxic
clinical
effects
or
neuropathology.
The
assessment
of
hydrogen
cyanide
neurotoxicity
was
based
on
studies
conducted
with
hydrogen
cyanide,
potassium
cyanide,
sodium
cyanide,
and
cyanogen.

4.2.2.1
Behavioral
Study
in
Pigs
The
effects
of
cyanide
on
behavior
were
studied
in
fasted
25­
week
old
miniature
pigs
(
12
litter
mates:
5
females
and
7
castrated
males)
randomized
in
four
groups
(
Jackson,
1988).
The
animals
were
dosed
daily
for
24
weeks
with
a
single
bolus
of
cyanide
as
aqueous
potassium
cyanide
just
prior
to
daily
feeding.
The
doses
were
0,
0.4,
0.7,
or
1.2
mg
cyanide/
kg
BW,
chosen
to
be
equivalent
to
those
consumed
by
West
Africans
in
their
diet.
Every
six
weeks,
thyroid
function
(
T3
and
T4)
and
fasting
blood
glucose
were
measured,
but
not
thyroid­
stimulating
hormone
(
TSH).
Daily
observations
were
made
of
clinical
signs
and
various
behavioral
measurements,
including
social,
antagonistic,
exploratory,
learning,
feeding,
and
excretory
behavior.
In
all
treatment
groups,
dose
related
decreases
were
evident
from
week
6
in
blood
levels
of
T3
and
T4
and
an
increase
in
fasting
blood
glucose
was
noted,
particularly
in
top­
dose
animals.
Statistical
analysis
was
not
provided
for
each
dose
group
versus
the
control,
but
changes
in
top
dose
animals
appeared
significant
by
week
18;
by
week
24,
decreases
of
35%
for
T3
and
15%
for
T4
and
an
increase
of
60%
in
fasting
blood
glucose
were
observed.
Behavioral
observations
revealed
a
picture
of
decreased
high­
energy
demanding
behavior,
such
as
exploration
and
aggression,
slower
eating,
more
frequent
drinking,
and
shivering
consistent
with
the
decreased
thyroid
activity.
A
LOAEL
of
0.5
mg
HCN/
kg
BW/
day
could
be
suggested
from
this
study.
It
is
important
to
note
major
weaknesses
of
this
study.
The
study
used
a
bolus
dose
with
consequent
high
peaks
of
cyanide
concentration
in
the
organism
and
involved
a
very
small
number
of
animals
(
three
animals
in
four
groups)
and
limited
statistical
analysis.
Page
20
of
44
4.2.2.2
Chronic
Toxicity
Study
in
Dogs
Dogs
administered
sodium
cyanide
in
capsules
at
levels
of
0,
0.5,
2,
or
1­
4
mg/
kg
BW
(
one
dog
at
each
dose
level)
daily
for
13­
15
months
showed
severe
signs
of
acute
cyanide
poisoning
right
after
the
daily
dosing
(
the
dog
at
the
lowest
dose
died).
In
the
autopsy,
the
only
significant
finding
were
degenerative
changes
in
the
ganglia
cells
of
the
central
nervous
system,
interpreted
to
be
caused
by
multiple
episodes
of
acute
cerebral
hypoxia
(
Hertting
et
al,
1960).

4.2.2.3
Inhalation
Toxicity
Study
in
Monkeys
and
Rats
In
a
6
month
inhalation
toxicity
study
in
rhesus
monkeys
and
CD
rats,
Lewis,
Anger
and
Vault
(
1984)
exposed
groups
of
5
rhesus
monkeys
and
30
male
rats
for
6
hr/
day,
5
days/
week
to
(
A)
Control
group
(
B)
11
ppm
cyanogen
or
(
C)
25
ppm
cyanogen.
This
corresponded
to
25,
or
56
mg
hydrogen
cyanide/
m3.
At
the
outset
of
exposures,
there
was
a
doubling
of
the
rate
of
responding
on
a
variable
interval
2.9
min
schedule
of
reinforcement
in
monkeys
exposed
to
25
ppm
cyanogen,
and
increases
were
also
seen
in
the
monkeys
receiving
11
ppm
exposures;
the
increases
were
transitory
as
the
rate
returned
to
control
levels
before
exposures
were
terminated.
At
the
end
of
the
6
month
exposure
period,
there
were
no
effects
in
hematologic
or
clinical
chemistry
parameters
attributable
to
the
inhalation
exposure
to
cyanogen.
The
electrocardiograms,
and
gross
pathologic
and
histopathologic
examinations
of
test
animals
were
normal
when
compared
to
the
control
animals.
Total
lung
moisture
content
was
significantly
lower
in
monkeys
exposed
to
either
11
or
25
ppm
cyanogen
than
in
control
animals.
Body
weights
were
significantly
lower
in
rats
exposed
to
25
ppm
cyanogen
than
in
controls.
The
results
suggest
that
subchronic
25
ppm
cyanogen
exposures
are
marginally
toxic,
but
that
11
ppm
cyanogen
may
be
considered
a
no
adverse­
effect
level
(
NOAEL).
The
11
and
25
ppm
cyanogen
concentrations
corresponds
to
25
and
56
mg
HCN/
m3.

4.2.2.4
Other
Indications
of
Neurotoxic
Effects
Potentiation
to
noise­
induced
hearing
loss
by
exposure
of
rats
to
low
concentrations
of
hydrogen
cyanide
was
reported
by
Fechter
et
al
(
2002).
It
was
suggested
that
hydrogen
cyanide
(
34
mg/
m3
for
3.5
hours)
plus
noise
produced
impaired
auditory
function
by
producing
significant
oxidative
stress
in
the
cochlea.
Hydrogen
cyanide
alone
did
not
cause
significant
hearing
loss
or
hair
cell
loss
(
WHO,
2004).
A
single
intraperitoneal
dose
and
25
repeated
intraperitoneal
doses
of
sodium
cyanide
(
2
mg/
kg
(
1
mg
hydrogen
cyanide/
kg)),
stated
to
represent
25%
of
the
LD50,
administered
to
Wistar
strain
albino
rats
resulted
in
similar
reductions
of
memory
(
T­
maze
test),
along
with
reductions
in
the
level
of
dopamine
and
5­
hydroxytryptamine
and
increases
in
norepinephrine
and
epinephrine
levels
in
the
hippocampus,
measured
after
a
month
of
treatment
(
Mathangi
&
Namasivayam,
2000).
There
is
also
a
neuropathological
study
in
goats
(
Soto­
Blanco
et
al,
2002),
which
reported
ultrastructural
changes
in
animals
given
>
0.48
mg
cyanide/
kg
BW/
day
in
drinking
water
for
5
months.
However
this
study
did
not
present
quantitative
data
or
statistical
analysis,
since
it
was
essentially
a
morphometric
evaluation.
Page
21
of
44
4.2.3
Developmental
Toxicity
Studies
There
are
no
developmental
toxicity
studies
available
for
hydrogen
cyanide.
Developmental
studies
with
sodium
cyanide,
cassava
meal/
powder
(
cassava
plant
contains
a
cyanogen
called
linamarin),
cyanogenic
glycoside
linamarin,
amygdalin,
and
acetone
cyanohydrin
were
available
and
reviewed
for
this
assessment.
The
weight
of
the
evidence
of
available
data
indicates
that
cyanide
induces
developmental
effects
only
at
doses
or
concentrations
that
are
overtly
toxic
to
the
maternal
animals.

4.2.3.1
Developmental
Toxicity
Studies
in
Hamsters
Preliminary
experiments
with
sodium
cyanide
given
to
pregnant
Golden
Syrian
hamsters
using
osmotic
minipumps
implanted
subcutaneously,
showed
that
at
a
dose
rate
of
0.125
mmol/
kg
BW/
hour,
no
effects
on
the
fetus
were
observed,
while
at
a
dose
rate
of
0.133
mmol/
kg
BW/
hour
or
more,
there
was
a
100%
resorption
rate
and
maternal
deaths.
Toxicity
to
dams
increased
with
increasing
dose
levels
and
included
dyspnea,
ataxia,
reduced
body
temperature,
and
loss
of
body
weight.
Co­
administration
of
thiosulfate
eliminated
the
teratogenic
effect,
protecting
the
dams
and
fetuses
from
the
toxic
effects
of
cyanide
(
Doherty
et
al,
1982).

In
a
follow­
up
experiment,
pregnant
Golden
Syrian
hamsters
(
5­
7
per
group)
were
continuously
exposed
to
sodium
cyanide
from
day
6
to
day
9
of
gestation
at
0,
0.126,
0.1275,
or
0.1295
mmol/
kg
BW/
hour
using
osmotic
minipumps
implanted
subcutaneously.
These
doses
are
equivalent
to
0,
78.7,
79.6,
and
80.9
mg/
kg
BW/
day.
Toxicity
to
dams
increased
with
increasing
dose
levels
and
included
salivation,
dyspnea,
ataxia,
reduced
body
temperature,
and
loss
of
body
weight.
The
treatment
induced
a
remarkable
increase
in
resorptions
as
well
as
fetal
malformations.
These
included
non­
closure
of
the
neural
tube,
exencephaly,
encephalocoele,
and
malformations
of
the
heart,
limbs
or
tail.
Co­
administration
of
thiosulfate
eliminated
the
teratogenic
effect,
protecting
the
dams
and
fetuses
from
the
toxic
effects
of
cyanide
(
Doherty
et
al,
1982).

Groups
of
pregnant
hamsters
were
fed
diets
consisting
of
two
types
of
cassava
meal,
either
a
"
low­
cyanide"
(
sweet
cassava
meal)
or
a
"
high­
cyanide"
(
bitter
cassava
meal)
variety.
These
were
mixed
(
80:
20)
with
laboratory
chow
and
administered
on
days
3­
14
of
gestation
(
Frakes
et
al,
1986).
The
cyanide
concentration
of
the
sweet
cassava
meals
was
0.6­
0.7
mmol/
kg;
that
of
the
bitter
cassava
meal
was
5­
11
(
mean
7.9)
mmol/
kg.
Cassava
fed
dams
gained
significantly
less
weight
than
did
control
animals
(
fed
diet
similar
in
nutritional
values
as
cassava,
but
without
cyanogenic
glycosides)
and
their
offspring
showed
evidence
of
fetotoxicity
(
reduced
fetal
body
weight
and
reduced
ossification
of
sacrocaudal
vertebrae,
metatarsals
and
sternebrae).
The
bitter
cassava
also
produced
a
significant
increase
in
the
number
of
runts
compared
with
litters
from
dams
fed
either
low­
protein
or
laboratory­
stock
diets.
The
only
teratogenic
effects
noted
were
hydrocephalus
in
three
animals
in
the
low­
cyanide
(
sweet
cassava)
test
group
and
one
encephalocoele
found
in
one
animal
at
the
high­
cyanide
(
bitter
cassava)
test
group.
Page
22
of
44
Additionally,
Frakes
et
al
(
1985)
studied
the
developmental
toxicity
of
the
cyanogenic
glycoside
linamarin
in
the
golden
hamster
at
doses
of
0,
70,
100,
120,
or
140
mg/
kg.
This
dosing
regiment
resulted
in
an
increased
incidence
of
vertebral
and
rib
anomalies
as
well
as
the
production
of
encephalocoele
in
the
offspring
at
a
dose
of
120
or
140
mg/
kg
BW,
which
was
a
maternally
toxic
dose.
The
developmental
LOAEL
was
estimated
to
be
120
mg/
kg/
day
based
on
skeletal
effects
and
the
maternal
LOAEL
was
estimated
to
be
100
mg/
kg
concentration
based
on
cyanide
intoxication
(
dyspnea,
tremors,
ataxia,
etc.).
A
NOAEL
was
established
for
linamarin
fetal
and
maternal
effects
at
100
mg/
kg
and
70
mg/
kg,
respectively,
in
the
study.
Frakes
et
al
(
1985)
estimates
that
a
50
kg
person
would
have
to
consume
about
2.7
kg
of
cassava
flour
containing
200
mg/
kg
HCN
in
order
to
receive
a
dose
of
linamarin
equal
to
the
100
mg/
kg
dose
used
in
the
study.
Therefore,
ingestion
of
a
toxic/
teratogenic
dose
of
linamarin
by
a
human
female
seems
unlikely.

A
single
oral
dose
of
d/
l­
amygdalin
at
gestational
day
8
resulted
in
exencephaly,
encephalocoele,
and
skeletal
malformations
at
doses
of
>
250
mg/
kg
(>
14
mg
cyanide/
kg)
in
hamsters
(
these
doses
were
also
clearly
toxic
to
the
mothers).
At
the
lowest
dose
tested,
200
mg/
kg
(
11
mg
cyanide/
kg),
fused
ribs
were
observed
in
two
offspring
of
one
mother
(
maternal
toxicity
not
reported).
Encephalocoele
and
rib
anomalies
were
also
reported
after
a
dose
of
dprunasin
(
177
mg/
kg
(
16
mg
cyanide/
kg))
in
the
absence
of
maternal
toxicity
in
hamsters.
No
teratogenic
effects
were
noted
when
hamsters
received
d/
l­
amygdalin
(
275
mg/
kg
(
16
mg
cyanide/
kg))
intravenously
(
WHO,
2004).
The
teratogenic
effects
found
were
considered
to
be
due
to
cyanide
released
by
bacterial
beta­
glucosidase
in
the
gastrointestinal
tract
(
Willhite,
1982).

4.2.3.2
Developmental
Toxicity
Study
in
Rats
Singh
(
1981)
reported
a
28%
increased
incidence
of
open
eye,
microcephaly,
limb
defects,
and
growth
retardation
in
the
offspring
of
pregnant
rats
fed
80%
milled
cassava
powder
during
the
first
15
days
of
gestation.
In
the
preliminary
study
with
limited
experimental
detail,
pregnant
albino
rats
were
fed
milled
cassava
powder
as
50%
and
80%
of
their
diet
during
the
fifteen
days
of
gestation.
Growth
retardation
and
an
increased
frequency
of
resorptions
were
observed
at
both
dose
levels;
in
addition,
limb
defects
were
observed
at
the
high
dose.
The
weight
gain
of
the
dams
was
lowered
from
day
6
onward;
no
further
information
on
maternal
toxicity
was
given.
No
indication
of
the
cyanide
content
of
the
cassava
was
given.

Groups
of
25
pregnant
Sprague­
Dawley
rats
were
dosed
by
gavage
on
days
6­
15
of
gestation
with
0,
1,
3,
or
10mg
acetone
cyanohydrin
/
kg
BW
(
equivalent
to
0,
0.3,
0.9,
or
3
mg
cyanide/
kg)
(
Monsanto
Co.,
1982).
Maternal
toxicity
was
evidenced
by
slight
reductions
in
body
weight
gain
in
the
mid­
and
high­
exposure
groups,
and
statistically
significant
differences
between
the
high­
dose
group
and
controls
were
found
for
the
number
of
corpora
lutea
implantations
per
dam.
There
were
no
comparable
differences
in
the
number
of
viable
fetuses
per
dam,
postimplantation
losses
per
dam,
mean
fetal
body
weight,
or
fetal
sex
distribution
for
all
dose
groups
and
the
controls.
The
incidences
of
fetal
malformations
and
developmental
variations
for
all
fetuses
of
treated
animals
and
controls
were
also
comparable.
It
was
concluded
that
10
mg
Page
23
of
44
ACH/
kg
BW
(
3
mg
cyanide/
kg)
was
not
teratogenic
in
the
rat
in
the
presence
of
maternal
toxicity
(
Monsanto
Co.,
1982,
1983a,
WHO,
2004).

4.2.4
Reproductive
Toxicity
Studies
There
are
relatively
few
data
available
on
the
reproductive
toxicity
of
cyanides.
There
are
no
reproductive
toxicity
studies
available
for
hydrogen
cyanide.
Reproductive
studies
with
sodium
cyanide,
potassium
cyanide,
cassava,
and
acetone
cyanohydrin
were
available
and
reviewed
for
this
assessment.

4.2.4.1
Reproductive
Toxicity
Studies
in
Rats
A
subchronic,
13­
week
repeated
dose
toxicity
study
was
conducted
in
which
sodium
cyanide
was
administered
in
the
drinking
water
(
NTP,
1993)
at
doses
of
0,
0.2,
0.5,
1.4,
4.5,
and
12.5
mg/
kg
BW/
day
for
males
and
0,
0.2,
1.7,
4.9,
and
12.5
mg/
kg
BW/
day
for
female
rats
and
0,
0.3,
1,
3,
9,
and
26
mg/
kg
BW/
day
for
mice.
There
were
no
deaths,
clinical
signs
associated
with
CNS
effects,
body
or
organ
weights,
or
histopathological
effects
in
the
brain
or
thyroid
of
rats
exposed
to
doses
up
to
12.5
mg/
kg
BW/
day,
respectively.
At
the
LOAEL
of
12.5
mg/
kg
BW/
day
in
rats,
there
were
slight
changes
in
the
reproductive
tract
of
male
rats
including
decreased
left
epididymis
weight,
left
caudal
epididymis
weight,
left
testis
weight,
spermatids
heads,
and
spermatid
counts
which,
although
they
apparently
did
not
affect
the
fertility
in
rats,
are
possibly
significant
to
humans.
The
NOAEL
for
these
effects
in
male
rats
was
4.5
mg/
kg
BW/
day.
The
examination
of
neurotoxicity
in
this
study
was
limited
to
clinical
observations
and
optical
microscopy
at
autopsy.
At
4.9
and
12.5
mg/
kg
BW/
day,
there
was
an
increase
in
the
time
spent
by
female
rats
in
proestrus
and
diestrus
relative
to
estrus
and
metestrus.
The
finding
in
female
rats
were
not
considered
adverse.
In
male
mice,
there
was
a
statistically
significant
decrease
in
epidiymidis
weight
at
26
mg/
kg
BW/
day,
but
no
changes
in
sperm
motility
or
spermatid
head
density
were
observed.
No
estrus
effects
were
seen
in
female
mice.
The
overall
NOAEL
for
the
NTP
study
was
selected
as
4.5
mg/
kg
BW/
day,
based
on
findings
in
the
male
reproductive
tract
at
the
LOAEL
of
12.5
mg/
kg
BW/
day
After
2
weeks
on
a
diet
containing
5
or
10
g
potassium
cyanide
/
100
g
of
diet,
female
rats
(
10/
group)
were
mated
with
untreated
males
(
Olusi
et
al,
1979).
No
pregnancies
resulted.
The
dose
corresponds
to
roughly
1000
and
2000
mg
cyanide/
kg
BW
/
day.
There
was
a
dosedependent
decrease
in
body
weight
gain,
blood
hemoglobin
(
18%
and
23%)
and
serum
T4
concentration
(
54%
and
75%).

In
a
male
fertility
study
(
Monsanto
Co.,
1985a),
Sprague­
Dawley
rats
(
n
=
15)
were
exposed
by
inhalation
to
acetone
cyanohydrin
(
0,
35,
101,
or
202
mg/
m3;
0,
11,
32,
or
64
mg
HCN/
m3)
6
hours/
day,
5
days/
week,
during
a
period
of
69
days
(
i.
e.,
48
exposure
days).
After
the
treatment
period,
the
males
were
mated
with
three
non­
exposed
females
each.
There
were
no
deaths,
clinical
signs
of
toxicity,
changes
in
body
weight,
or
changes
in
gross
necropsy
after
48
exposures
to
up
to
202
mg
acetone
cyanohydrin
(
64
mg
hydrogen
cyanide/
m3).
The
mating
Page
24
of
44
efficiency,
number
of
live
implants,
and
pre­
and
post­
implantation
losses
were
not
different
between
treated
and
control
groups
(
WHO,
2004).

Female
Sprague­
Dawley
rats
were
exposed
by
inhalation
(
6
hours/
day,
7
days/
week)
for
21
days
to
acetone
cyanohydrin
at
38,
108,
and
207
mg/
m3
and
then
mated
to
untreated
males.
Exposure
of
the
females,
which
was
equivalent
to
12,
34,
and
66
mg
hydrogen
cyanide/
m3,
was
continued
until
the
day
of
mating,
and
the
females
were
sacrificed
at
mid­
gestation
(
gestation
days
13­
15).
No
treatment­
related
effects
on
female
clinical
signs
of
toxicity,
mortality,
body
weight
gain
or
gross
necropsy
during
or
after
34­
36
exposures
up
to
207
mg
acetone
cyanohydrin/
m3
(
66
mg
hydrogen
cyanide/
m3).
Additionally,
no
treatment­
related
effects
on
female
fertility
were
observed
in
any
of
the
exposure
groups.
The
only
frequently
observed
clinical
sign
post­
exposure
was
red
nasal
discharge
or
encrustation.
The
highest
exposure
in
the
study
(
207
mg
acetone
cyanohydrin/
m3)
could
be
considered
as
the
NOAEL
for
female
reproductive
effects
(
Monsanto,
1985b,
WHO,
2004).

In
a
study
on
the
long­
term
and
carry­
over
effect
of
control
and
500
ppm
dietary
potassium
added
to
a
cassava
root
flour­
based
basal
diet
in
the
life
cycle
performance
and
metabolism
of
Wistar
rats,
Tewe
and
Maner
(
1981a)
demonstrated
that
there
was
no
marked
effect
in
gestation
and
lactation
performance
in
female
rats.
No
carry­
over
effect
of
the
cyanide
treated
diet
fed
during
gestation
was
observed
on
lactation
performance
of
female
rats,
although
females
exposed
to
fortified
diets
gained
less
weight
than
controls.
However,
the
high
cyanidecontaining
diet
significantly
reduced
the
food
consumption
and
growth
of
offspring
when
fed
during
the
post­
weaning
growth
period.
Serum
thiocyanate
was
significantly
increased
in
the
potassium
cyanide
group
in
lactating
rats
and
their
offspring
during
lactation
and
in
the
postweaning
growth
phase
of
the
pups.
Rhodenase,
the
enzyme
which
converts
cyanide
to
thiocyanate,
activity
in
liver
and
kidney
was
unaffected
by
feeding
the
high
cyanide
diet
during
gestation,
lactation,
and/
or
during
post­
weaning
growth.

4.2.4.2
Reproductive
Toxicity
Study
in
Pigs
In
a
second
study
by
Tewe
and
Maner
(
1981b),
groups
of
six
pregnant
Yorkshire
pigs
were
fed
fresh
cassava
diets
containing
0,
250,
and
500
ppm
of
potassium
cyanide.
Dietary
cyanide
level
had
no
significant
effect
on
either
the
number
or
weight
of
110­
day
old
fetuses.
Serum
thiocyanate
concentration
was
slightly
but
not
significantly
increased
in
the
500
ppm
cyanide
group
and
serum
PBI
decreased
during
gestation
in
all
maternal
groups,
including
controls.
Fetal
serum
thiocyanate
concentration
was
significantly
higher
(
p<
0.05)
in
the
group
fed
500
ppm
added
cyanide.
A
small
increase
in
maternal
thyroid
weight
with
increasing
level
of
cyanide
was
observed.
Pathological
studies
showed
proliferation
of
glomerular
cells
of
the
kidney
in
maternal
animals
in
all
groups,
including
controls.
Both
slaughtered
500
ppm
"
gilts"
­
maternal
animals
­
had
thyroid
glands
with
epithelial
follicular
cells
which
were
low
in
height
and
had
an
accumulation
of
colloid.
In
the
presence
of
maternal
histopathologic
effects
to
the
thyroid
and
kidney,
fetal
spleen
and
heart
to
body
weight
ratios
were
decreased.
Cyanide
fed
during
gestation
did
not
affect
the
production
or
lactation
of
the
first
litter
of
offspring,
although
metabolic
and
Page
25
of
44
pathologic
differences
did
occur.
Milk
thiocyanate
and
colostrum
iodine
concentrations
were
significantly
higher
(
p<
0.05)
in
the
group
fed
500
ppm
cyanide.

4.2.5
Pre­
and/
or
Postnatal
Toxicity
4.2.5.1
Determination
of
Susceptibility
Significant
developmental
effects
from
exposure
to
cyanides
have
been
observed
across
species,
but
appear
in
the
presence
of
serious
overt
maternal
toxicity,
including
death.
There
is
no
quantitative
or
qualitative
increased
susceptibility
of
fetuses
and
offspring
across
species
in
comparison
to
maternal
and
parental
animals.
Serious
offspring
developmental
effects
of
the
CNS
have
also
been
associated
with
acute
maternal
CNS
clinical
findings,
as
well
as
other
maternal
effects
(
death,
dyspnea,
tremors,
ataxia,
decreased
body
weight,
etc.).
There
was
no
qualitative
or
quantitative
increased
susceptibility
in
postnatal
offspring
toxicity,
since
both
offspring
and
parental
effects
occurred
at
similar
toxic
dose
levels.

4.2.5.2
Degree
of
Concern
Analysis
and
Residual
Uncertainties
for
Pre
and/
or
Post­
natal
Susceptibility
There
are
no
quantitative
or
qualitative
increased
susceptibilities
associated
with
the
serious
offspring
and
parental
findings
resulting
from
exposure
to
cyanides.
These
results
indicate
low
residual
concern
due
to
the
fact
that
the
developmental
and
postnatal
findings
occurred
in
the
presence
of
maternal/
parental
effects.

4.2.6
Recommendation
for
a
Developmental
Neurotoxicity
Study
There
is
not
a
concern
for
developmental
neurotoxicity
resulting
from
exposure
to
Hydrogen
cyanide.
There
is
a
concern
for
serious
neurotoxic
findings
in
both
offspring
and
maternal
animals
i.
e.,
hydrogen
cyanide
is
a
neurotoxic
chemical
which
produces
neurotoxic
clinical
signs
in
both
offspring
and
maternal
animals
and
there
is
evidence
of
neuropathology
resulting
from
exposure
to
hydrogen
cyanide
in
both
offspring
and
maternal
animals.
However,
there
is
no
evidence
of
increased
susceptibility
in
the
several
developmental
and
reproduction
studies.
Therefore,
since
the
neuropathology
seen
in
offspring
in
both
developmental
and
reproduction
studies
is
a
result
of
the
acute
effects
of
cyanide
which
are
also
seen
in
adult
animals
a
developmental
neurotoxicity
study
is
not
required
for
hydrogen
cyanide
at
this
time.
Page
26
of
44
4.3
FQPA
Safety
Factor
There
was
no
qualitative
or
quantitative
increased
susceptibility
in
postnatal
offspring
toxicity,
since
both
offspring
and
parental
effects
occurred
at
similar
toxic
dose
levels.
Similarly,
there
is
low
residual
concern
due
to
the
fact
that
the
developmental
and
postnatal
findings
occurred
in
the
presence
of
maternal/
parental
effects.
Additionally,
the
mechanism
of
action
for
hydrogen
cyanide
toxicity
is
well
established.
Hydrogen
cyanide
binds
with
cytochrome
oxidase
in
the
electron
transport
system
and
inhibits
the
exchange
of
oxygen
from
the
blood
to
the
tissues
by
competitive
inhibition.
Since
the
cytochrome
oxidase
system
is
fully
functional
in
newborns,
offspring
and
parental
effects
would
occur
at
similar
toxic
dose
levels.
Therefore,
it
is
recommended
that
the
FQPA
safety
factor
be
reduced
to
1x
for
the
hydrogen
cyanide
risk
assessment.

4.4
Hazard
Identification
and
Toxicity
Endpoint
Selection
4.4.1
Acute
Reference
Dose
(
aRfD)
­
General
Population
Selection
of
an
acute
RfD
for
hydrogen
cyanide
was
based
on
published
data
from
a
clinical
trial
of
amygdalin
(
Laetrile)
in
the
treatment
of
human
cancer
(
Moertel,
CG
et
al.
1982
(
MRIDs
Nos
46769602,
46769601).
One
hundred
seventy­
eight
patients
with
cancer
were
treated
with
amygdalin
(
Laetrile)
plus
a
"
metabolic
therapy"
program
consisting
of
diet,
enzymes
and
vitamins.
Amygdalin
was
administered
at
an
intravenous
dose
of
4.5
g/
m2
of
body
surface
area
/
day
for
21
days
in
the
Standard
Dose
or
7
g/
m2
of
body
surface
area
/
day
for
21
days
at
the
High
Dose.
Following
intravenous
treatment,
amygdalin
was
administered
orally
at
0.5
g,
three
times
daily
at
the
Standard
Dose
Regimen
or
0.5
g,
four
times
daily
at
the
High
Dose
Regimen.
All
patients
were
fully
informed
about
the
experimental
and
unorthodox
nature
of
the
treatment
program
as
well
as
any
possible
alternative
treatment
available
to
them.
No
placebo
group
was
administered.
Clinical
signs
and
symptoms
consisting
of
nausea,
vomiting,
headaches,
dizziness,
mental
obtundation
and,
on
a
few
occasions,
dermatitis,
occurred
in
some
patients
on
occasion
following
a
single
0.5
g
oral
dose
of
amygdalin
or
when
two
0.5
g
oral
doses
were
administered
at
the
same
time,
or
shortly
apart,
to
compensate
for
a
missed
dose
or
in
one
patient
who
consumed
raw
almonds
following
oral
therapy
(
Moertel
et
al,
1981).
Blood
levels
of
patients
who
received
a
single
dose
ranged
between
1­
2
µ
gCN/
ml
whole
blood.
Blood
levels
of
cyanide
rose
to
2­
3
µ
gCN/
ml
when
the
single
0.5
g
dose
was
doubled
to
two
0.5
g
doses
at
an
administration.
These
increased
blood
levels
were
associated
with
an
increase
in
the
incidence
and
severity
of
some
of
the
toxic
signs
and
symptoms
due
to
the
release
of
Hydrogen
cyanide
from
amygdalin
by
the
enzymatic
action
of
B­
glucosidase,
an
intestinal
enzyme.
If
the
blood
cyanide
level
was
found
to
be
3
µ
gCN/
ml
or
greater
at
any
time,
therapy
was
permanently
discontinued.
Therefore,
the
single
dose
of
0.5
g
of
amygdalin
was
determined
to
be
a
minimally
toxic
dose,
whereas
the
double
dose
was
generally
regarded
as
frankly
toxic.
No
substantive
benefit
was
observed
in
terms
of
cure,
improvement,
or
stabilization
of
cancer,
or
extension
of
life
span.
Amygdalin
(
laetrile)
is
a
toxic
drug
that
is
not
effective
as
a
cancer
treatment.
In
the
Standard
Dose
study,
a
single
dose
0.5
g
of
amygdalin
results
in
29.4
mg
of
Hydrogen
cyanide
(
500
mg/
17.1
mw
of
laetrile/
hydrogen
Page
27
of
44
cyanide
=
29.4
mg
of
HCN).
When
the
Hydrogen
cyanide
content
is
divided
by
the
approximate
BW
of
70
kg,
the
result
is
0.4
mg/
kg
BW/
day.

Supporting
evidence
comes
from
the
1956
Quarterly
Report
of
the
FDA,
which
demonstrates
that
total
oral
doses
of
20
to
30
mg
NaCN
(
the
equivalent
of
11.0
to
16.5
mg
hydrogen
cyanide
or
0.2
mg
HCN/
kg
BW)
have
been
administered
to
man
to
demonstrate
thiocyanate
in
saliva.
This
total
oral
dose
level
(
0.2
mg/
kg
BW)
has
been
estimated
as
a
NOAEL
in
comparison
to
the
human
LOAEL
for
mortality
of
0.56
­
1.0
mg/
kg
BW.

The
single
oral
dose
level
of
0.4
mg/
kg/
BW
for
HCN
has
therefore
been
identified
as
a
LOAEL
in
comparison
to
the
estimated
hydrogen
cyanide
human
NOAEL
of
0.2
mg/
kg
BW
for
thiocyanate
determinations
in
human
saliva
(
FDA
1956)
and
the
LOAEL
for
cyanide
mortality
of
0.56­
1.0
mg/
kg
BW.

Dose
and
Endpoint
for
Establishing
aRfD:
0.4
mg/
kg
BW/
day
LOAEL
based
on
symptoms
and
clinical
signs
of
hydrogen
cyanide
toxicity
Uncertainty
Factor
(
UF):
100
(
10X
for
intraspecies
variations
and
10X
for
steep
doseresponse
curve,
severity
of
effects,
and
lack
of
a
NOAEL.

Comments
about
Study/
Endpoint/
Uncertainty
Factor:
The
Moertel
clinical
trial
study
arrived
at
the
dose
of
amygdalin
(
0.5
g)
that
results
in
clinical
signs
in
humans.
The
estimated
human
dose
of
0.4
mg/
kg
BW
can
be
used
for
risk
assessment
purposes.
The
uncertainty
factor
of
100
incorporates
10X
for
intraspecies
variations
and
10X
for
lack
of
a
NOAEL,
severity
of
effects,
and
a
steep
dose­
response
curve.

4.4.2
Chronic
Reference
Dose
(
cRfD)

A
chronic
RfD
was
not
selected
because
the
range
of
appropriate
systemic
NOAELs
in
mammalian
species
is
from
4.5
­
15
mg
HCN/
kg
BW/
day.
These
NOAELs
far
exceed
the
estimated
human
LOAEL
of
0.4
mg/
kg
BW
used
for
the
acute
dietary
RfD.
If
these
substantially
higher
NOAELs
were
used
for
the
cRfD,
they
would
result
in
chronic
exposures
which
would
be
greater
than
and
possibly
lethal
in
comparison
to
an
acute
dose.
A
summary
of
these
mammalian
studies
is
presented
as
follows:

The
chronic
ingestion
of
food
fumigated
with
Hydrogen
cyanide
and
containing
residues
up
to
300
ppm
has
been
fed
to
10
rats/
sex/
dose
in
a
2­
year
feeding
study
(
Howard
and
Hanzal,
1955).
There
were
no
systemic
effects,
including
neurotoxicity,
up
to
the
highest
dose
tested
of
300
ppm
in
the
food.
Based
on
the
food
intake
and
body
weight
of
young
and
old
rats,
the
Acute
RfD
(
General
population)
=
0.4
mg/
kg
(
LOAEL)
=
0.004
mg/
kg
100
(
UF)
Page
28
of
44
estimated
dietary
NOAEL
was
10.8
mg/
kg
BW/
day.
Since
the
acute
oral
fatal
dose
of
potassium
cyanide
for
rats
is
between
10­
15
mg/
kg
BW
(
Handbook
of
Toxicology,
(
1956)),
yielding
4.0
to
6.0
mg/
kg
BW
Hydrogen
cyanide,
the
rats
in
the
2­
year
study
ingested
1.8
to
2.7
times
the
fatal
dose
of
hydrogen
cyanide
each
day
throughout
their
lifetime
without
any
measurable
effects.
Virtually
no
cyanide
was
found
in
plasma
and
kidneys.
Low
levels
were
found
in
erythrocytes
(
mean
of
1.9
µ
g/
100g).
In
the
2­
year
rat
feeding
study,
residues
of
thiocyanate,
the
less
toxic
primary
liver
metabolite
of
cyanide,
increased
3.5­
fold
in
plasma,
3.3­
fold
in
erythrocytes,
1.3­
fold
in
liver,
and
2.5­
fold
in
kidneys
of
the
rats
exposed
to
Hydrogen
cyanide
in
the
diet
(
Howard
and
Hanzal,
1955).

The
systemic
NOAEL
of
10.8
mg/
kg
BW/
day
in
the
2­
year
study
in
rats
provides
data
which
are
supported
by
the
results
and
NOAELs
of
other
available
studies.

In
the
13
week
repeated­
dose
toxicity
study
(
NTP,
1993)
in
which
sodium
cyanide
was
administered
in
the
drinking
water,
there
were
no
mortalities
or
clinical
signs
(
associated
with
central
nervous
system
effects)
or
histopathological
effects
in
the
brain,
thyroid,
or
other
organs
of
rats
and
mice
exposed
to
doses
up
to
12.5
and
26
mg/
kg
BW/
day,
respectively.
The
reproductive
tract
in
males
was
the
most
sensitive
organ
to
cyanide
exposure
in
this
study:
In
rats
at
12.5
mg/
kg
BW/
day,
there
were
lowered
weight
of
testis
and
epididymis,
together
with
a
decrease
in
the
number
of
spermatid
heads
in
the
testis
and
decreased
motility
of
epididymal
sperm.
The
NOAEL
in
this
study,
4.5
mg/
kg
BW/
day,
is
consistent
with
the
2­
year
study
in
rats
which
had
a
NOAEL
of
10.8
mg/
kg
BW/
day
(
Howard
and
Hanzal,
1955).

These
results
are
also
roughly
consistent
with
the
NOAEL
in
the
14
week
inhalation
study
(
Monsanto
Co.,
1984a)
in
which
the
airborne
systemic
no­
effect
level
of
204
mg
acetone
cyanohydrin
(
ACH)/
m3
can
be
estimated
to
correspond
to
a
daily
dose
of
approximately
15
mg
HCN/
kg
BW/
day.

The
other
available
studies
specifically
intended
to
investigate
neurotoxicity
or
other
effects
of
cyanides
have
major
weaknesses:
the
study
in
miniature
pigs
(
Jackson,
1988),
which
reported
slight
functional
thyroid
changes
and
behavioral
aberrations
at
1.2
mg
cyanide/
kg
BW/
day,
used
a
bolus
dose
with
consequent
high
peaks
of
cyanide
concentration
in
the
organism
and
involved
a
very
small
number
of
animals
(
three
animals
in
four
groups)
and
limited
statistical
analysis.
Similarly,
the
neuropathological
study
in
goats
(
Soto­
Blanco
et
al,
2002),
which
reported
ultrastructural
changes
in
animals
given
>
0.48
mg
cyanide/
kg
BW/
day
in
drinking
water
for
5
months,
did
not
present
quantitative
data
or
statistical
analysis,
since
it
was
essentially
a
morphometric
evaluation.

Studies
by
Philbrick
et
al
(
1979)
showed
decreased
weight
gain
and
thyroxin
levels
and
myelin
degeneration
in
rats
(
10
males/
dose,
females
were
not
investigated)
fed
CN
for
one
year
at
the
LOAEL
of
30
mg/
kg
BW/
day
(
only
dose
tested).
A
NOAEL
was
not
established.
Page
29
of
44
4.4.3
Dermal
Absorption
Dermal
absorption
of
Hydrogen
cyanide
is
much
slower
than
pulmonary
absorption,
and
the
amount
and
speed
of
absorption
through
human
skin
are
dependent
on
the
amount
of
skin
moisture
and
duration
of
skin
contact.
There
are
no
adequate
dermal
penetration
studies
with
hydrogen
cyanide.
Since
dermal
exposure
is
not
expected
based
on
the
use
pattern,
a
dermal
assessment
was
not
conducted
and
a
dermal
absorption
factor
was
not
required
for
this
assessment.

4.4.4
Dermal
Exposure
(
All
Durations)

Worker
and
residential
dermal
exposures
are
not
expected
based
on
use
patterns
and
restrictions
and
were
therefore
not
assessed
for
this
TRED.

4.4.5
Inhalation
Exposure
(
All
Durations)

The
inhalation
endpoint
for
all
exposure
durations
was
selected
based
on
a
subchronic
inhalation
toxicity
study
in
rats.
In
this
study,
Sprague­
Dawley
rats
(
15/
sex/
dose)
were
exposed
to
acetone
cyanohydrin
(
ACH)
[
which
is
rapidly
hydrolyzed
to
hydrogen
cyanide
at
physiological
pH]
at
concentrations
of
0,
36,
101,
or
204
mg
ACH/
m3
for
6
hours/
day,
5
days/
week,
for
14
weeks.
The
exposures
were
equivalent
to
0,
11,
32,
and
65
mg
HCN/
m3
(
Monsanto
Co.,
1984a).
There
were
no
treatment­
related
deaths
or
effects
in
body
weight
or
hematology.
Irritation
of
the
nose
and
eyes
was
observed,
but
no
more
in
exposed
than
in
non­
exposed
animals.
A
decrease
in
blood
glucose
was
recorded
in
mid
and
high
dose
females
and
a
decrease
in
total
serum
protein
and
globulin
was
noted
in
mid­
and
low­
dose
females.
There
were
no
effects
in
serum
T3
or
T4
and
histopathology.
The
NOAEL
reported
from
the
study
was
204
mg
ACH/
m3,
corresponding
to
65
mg
HCN/
m3.
This
can
be
estimated
to
correspond
to
a
daily
dose
of
15
mg
cyanide/
kg
BW/
day.
However,
in
a
similar
4­
week
inhalation
study
at
an
average
ACH
concentration
of
211
mg
m3
(
67
mg
hydrogen
cyanide/
m3),
no
systemic
effects
were
observed,
except
on
the
first
day
of
exposure,
when
the
concentrations
in
the
chamber
fluctuated
and
reached
values
of
225
mg
ACH/
m3
(
71
mg
hydrogen
cyanide/
m3)
at
which
dose
3
out
of
10
animals
died
(
Monsanto
Co.,
1984a,
1985c).

Dose/
Endpoint
for
Risk
Assessment:
The
NOAEL
of
65
mg
HCN/
m3
based
on
mortality
in
3
of
10
rats
at
the
LOAEL
of
71
mg/
m3
(
HDT).
For
occupational
exposures,
the
inhalation
study
NOAEL
of
65
mg
HCN/
m3
(
60
ppm)
would
be
converted
to
human
equivalent
dose
of
50
mg
HCN/
m3
(
65
mg
HCN/
m3
x
(
6h/
8h)
assuming
similar
Regional
Gas
Distribution
Ratio
(
RGDR)
between
animals
and
humans
(
USEPA,
1994).

Comments
about
Study/
Endpoint:
The
NOAEL/
LOAEL
for
the
inhalation
endpoint
is
based
on
the
effect
of
mortality
for
hydrogen
cyanide.
The
MOE
is
based
on
the
uncertainty
factor
of
30X
(
3x
interspecies
factor
and
10x
intraspecies
factor).
The
traditional
interspecies
factor
of
10X
is
reduced
to
3X
since
the
doses
are
expressed
as
air
concentrations
and
the
Page
30
of
44
pharmacokinetics
is
assumed
similar
between
animals
and
humans.
The
interspecies
factor
of
3x
is
considered
sufficient
to
account
for
only
pharmacodynamic
differences
between
animals
and
humans.
An
additional
10X
for
steepness
of
dose
response/
severity
of
effect
was
considered
unnecessary
due
to
the
conservative
nature
of
the
selected
endpoint,
i.
e.,
a
subchronic
exposure
endpoint
is
used
to
assess
intermittent
short­
term
exposure.

4.4.6
Margins
of
Exposure
A
summary
of
target
Levels
of
Concern
for
risk
assessment
is
provided
in
Table
9.

Table
9.
Target
Levels
of
Concern/
Margin
of
Exposure
for
Hydrogen
Cyanide
Route/
Duration
Short­
Term
(
1­
30
Days)
Intermediate­
Term
(
1
­
6
Months)
Long­
Term
(>
6
Months)
Occupational
(
Worker)
Exposure
Dermal
N/
A
N/
A
N/
A
Inhalation
30
30
30
Residential
(
Non­
Dietary)
Exposure
Oral
N/
A
N/
A
N/
A
Dermal
N/
A
N/
A
N/
A
Inhalation
N/
A
N/
A
N/
A
The
uncertainty
factor
for
inhalation
exposure
is
30X
(
3x
interspecies
factor
and
10x
intraspecies
factor).
For
inhalation,
the
traditional
interspecies
factor
of
10X
is
reduced
to
3X
since
the
doses
are
expressed
as
air
concentrations
and
the
pharmacokinetics
is
assumed
similar
between
animals
and
humans.
The
interspecies
factor
of
3x
is
considered
sufficient
to
account
for
only
pharmacodynamic
differences
between
animals
and
humans.

4.4.7
Recommendation
for
Aggregate
Exposure
Risk
Assessments
Under
FQPA,
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
Since
there
are
no
residential
uses,
an
assessment
of
aggregate
exposure
from
risk
from
food
and
non­
food
sources
is
not
required.

4.4.8
Classification
of
Carcinogenic
Potential
The
classification
of
the
carcinogenic
potential
could
not
be
determined
due
to
the
absence
of
acceptable
cancer
studies
in
rats
and
mice.
Because
of
cyanide's
high
toxicity,
it
would
be
difficult
to
conduct
a
meaningful
cancer
study
in
rats
and
mice
over
a
two­
year
period.
In
addition,
regulation
of
cyanide's
acute
toxicity
is
considered
to
be
protective
for
potential
carcinogenicity
by
the
same
rationale
outlined
in
Section
4.4.2.
Hydrogen
cyanide
has
been
evaluated
for
mutagenic
potential
with
mixed
results
and
several
open
literature
references
are
available
(
Table
8).
Page
31
of
44
4.4.9
Summary
of
Endpoints
Selected
for
Risk
Assessment
Toxicological
doses/
endpoints
selected
for
the
hydrogen
cyanide
risk
assessment
are
provided
in
Table
10.

Table
10.
Summary
of
Toxicological
Doses
and
Endpoints
for
Chemical
for
Use
in
Human
Risk
Assessments
Exposure
Scenario
Dose
Used
in
Risk
Assessment,
UF
FQPA
SF*
and
Level
of
Concern
for
Risk
Assessment
Study
and
Toxicological
Effects
Acute
Dietary
(
general
population)
Oral
dose
of
29.4
mg
HCN
calculated
as
single
dose
LOAEL
of
0.4
mg/
kg/
day;
UF
=
100;
aRfD
=
0.004
mg/
kg/
day
FQPA
Safety
Factor
=
1
aPAD
=
0.004
mg/
kg/
day
Clinical
trial
study
in
humans,
Moertel
et
al
(
1982).
LOAEL
of
0.4
mg/
kg/
day
based
on
symptoms
and
clinical
signs
of
hydrogen
cyanide
toxicity
Inhalation
(
all
durations)
NOAEL
of
65
mg
HCN/
m3
(
60
ppm)
(
50
mg/
m3
or
46
ppm
adjusted
for
occupational
exposure)
MOE
requirement
=
30
Subchronic
(
14
weeks)
inhalation
study
with
LOAEL
of
71
mg
HCN/
m3
(
64
ppm)
based
on
mortality
in
3
of
10
rats
after
a
single
dose
Cancer
(
oral,
dermal,
inhalation)
Classification:
No
available
studies
UF
=
uncertainty
factor,
FQPA
SF
=
FQPA
safety
factor,
NOAEL
=
no
observed
adverse
effect
level,
LOAEL
=
lowest
observed
adverse
effect
level,
PAD
=
population
adjusted
dose
(
a
=
acute,
c
=
chronic)
RfD
=
reference
dose,
MOE
=
margin
of
exposure,
LOC
=
level
of
concern,
NA
=
Not
Applicable
Note:
Study
NOAEL
is
adjusted
to
human
equivalent
doses
for
occupational
scenario
only
e.
g.,
animal
NOAEL
of
65
mg/
m3
(
6h/
day,
5d/
week)
is
adjusted
to
human
NOAEL
of
50
mg/
m3
(
8
h/
day,
5d/
week),
assuming
the
regional
gas
dose
ratio
(
RGDR)
is
similar
between
animals
and
humans
(
65
ppm
x
6h/
8h
=
50
ppm)
(
USEPA,
1994).
*
Refer
to
Section
4.3
4.5
Endocrine
Disruption
EPA
is
required
under
the
FFDCA,
as
amended
by
FQPA,
to
develop
a
screening
program
to
determine
whether
certain
substances
(
including
all
pesticide
active
and
other
ingredients)
"
may
have
an
effect
in
humans
that
is
similar
to
an
effect
produced
by
a
naturally
occurring
estrogen,
or
other
such
endocrine
effects
as
the
Administrator
may
designate."
Following
recommendations
of
its
Endocrine
Disruptor
and
Testing
Advisory
Committee
(
EDSTAC),
EPA
determined
that
there
was
a
scientific
basis
for
including,
as
part
of
the
program,
the
androgen
and
thyroid
hormone
systems,
in
addition
to
the
estrogen
hormone
system.
EPA
also
adopted
EDSTAC's
recommendation
that
the
Program
include
evaluations
of
potential
effects
in
wildlife.
For
pesticide
chemicals,
EPA
will
use
FIFRA
and,
to
the
extent
that
effects
in
wildlife
may
help
determine
whether
a
substance
may
have
an
effect
in
humans,
FFDCA
authority
to
require
the
wildlife
evaluations.
As
the
science
develops
and
resources
allow,
screening
of
additional
hormone
systems
may
be
added
to
the
Endocrine
Disruptor
Screening
Program
(
EDSP).

In
the
available
toxicity
studies
on
hydrogen
cyanide,
there
was
no
estrogen
or
androgen,
mediated
toxicity.
Thyroid
effects
in
the
presence
of
liver
toxicity
were
seen
in
both
sexes
at
the
highest
dose
tested
in
the
chronic
dog
study.
When
additional
appropriate
screening
and/
or
Page
32
of
44
testing
protocols
being
considered
under
the
Agency's
EDSP
have
been
developed,
hydrogen
cyanide
may
be
subjected
to
further
screening
and/
or
testing
to
better
characterize
effects
related
to
endocrine
disruption.

5.0
PUBLIC
HEALTH
DATA
Only
five
reports
have
been
submitted
by
USDA
APHIS
concerning
mishaps
with
M­
44
Capsules
containing
sodium
cyanide
since
1992
when
EPA
set
up
the
Incident
Data
System.
None
of
the
mishaps
resulted
in
serious
medical
outcomes.
All
resulted
in
transient
symptoms
which
were
minor
to
moderate.
Poison
Control
Centers
have
tracked
rodenticide
use
of
cyanide
over
the
years
since
1985,
however,
their
system
does
not
specify
the
form
of
the
cyanide
(
e.
g.,
calcium
cyanide,
sodium
cyanide,
or
hydrogen
cyanide).
On
average
Poison
Control
Centers
receive
only
one
report
per
year.
Most
listed
the
outcome
as
not
determined
or,
at
most,
minor
medical
outcome.

6.0
DIETARY
EXPOSURE
ASSESSMENT
6.1
Dietary
Profile
A
tolerance
of
50
ppm
for
citrus
has
been
established
under
40
CFR
§
180.130
for
residues
of
hydrogen
cyanide
from
postharvest
fumigation
as
a
result
of
application
of
sodium
cyanide.
There
are
no
active
national
registrations
for
sodium
cyanide
with
food/
feed
uses.
However,
there
is
one
SLN
for
California
for
food/
feed
use
registration
for
sodium
cyanide.
Sodium
cyanide
is
used
in
California
as
a
source
of
hydrogen
cyanide
gas
to
control
red
scale
on
fresh
market
citrus
bound
for
Arizona.
The
SLN
end­
use
product
is
formulated
as
a
granular
containing
98%
sodium
cyanide
and
is
used
on
citrus
as
a
post­
harvest
fumigant.

6.1.1
Magnitude
of
the
Residue
in
Plants
and
Animals
In
a
recently
submitted
study
(
MRID
46868001),
residues
of
hydrogen
cyanide
in
orange
peel
averaged
1.2
ppm
8
hours
after
fumigation
with
1
ounce
sodium
cyanide/
100
ft3,
0.9
ppm
24
hours
after
fumigation,
and
0.45
ppm
48
hours
after
fumigation.
Residues
of
hydrogen
cyanide
in
orange
pulp
averaged
0.06
ppm
8
hours
after
fumigation,
0.02
ppm
24
hours
after
fumigation,
and
<
0.01
ppm
48
hours
after
fumigation.
Residues
in
whole
oranges
were
not
determined.
Additional
data
are
required
for
this
study.
Residue
data
from
an
additional
two
trials
are
required
along
with
residue
data
on
whole
oranges.
A
detailed
explanation
of
the
modifications
to
EPA
335.2
along
with
validation
of
this
method
at
the
reported
LOD
of
0.01
ppm
is
required.

Since
the
use
on
citrus
is
for
citrus
destined
for
the
fresh
market
in
Arizona
only,
the
8
hour
samples
were
not
used
in
the
dietary
exposure
analysis.
The
residue
data
for
the
24
and
48
hour
samples
will
be
used
to
refine
the
dietary
exposure
analysis.
The
average
residue
input
for
citrus
peel
in
DEEM
FCID
 
model
is
0.69
ppm
and
the
residue
input
for
citrus
pulp
is
0.013
ppm.
This
recently
submitted
residue
data
for
citrus
peel
and
citrus
edible
pulp
should
be
used
for
Page
33
of
44
the
dietary
exposure
analysis
instead
of
previously
submitted
data
which
did
not
reflect
residues
which
would
be
incurred
in/
on
pulp
and
peel.

6.1.2
Residue
Analytical
Method
The
residue
data
for
citrus
were
obtained
by
a
GLC
procedure
using
a
Coulson
electrolytic
nitrogen
detector
cell.
No
recovery
data
as
such
were
reported,
but
the
report
notes
that
virtually
all
the
Hydrogen
cyanide
gas
was
accounted
for
either
as
unabsorbed
gas
or
as
residues
in
the
treated
citrus.
In
effect,
recoveries
were
well
in
excess
of
95%.
Background
values
were
also
not
reported
as
such,
but
data
in
the
studies
indicated
blanks
(
residue
values
at
0
­
10
minutes)
to
be
of
the
order
of
1
ppm
or
less.
EPA's
response
to
the
citrus
petition
notes
that
the
method
is
adequate
for
obtaining
residue
data
or
as
an
alternate
enforcement
method
(
PP#
1E1124;
2/
17/
71;
W.
Cox).

The
enforcement
in
PAM,
Vol
II
is
a
titrimetric
method.
This
method
involves
the
distillation
of
Hydrogen
cyanide
from
acidified
substrate
into
an
alkaline
solution
followed
by
titration
with
silver
nitrate.
This
method
is
considered
adequate
to
determine
residues
of
1
ppm
or
more
(
PP#
1E1124;
2/
17/
71;
W.
Cox).

6.2
Drinking
Water
Profile
EFED
does
not
anticipate
significant
exposure
from
sodium
cyanide
or
hydrogen
cyanide
in
surface
water
and
ground
water
when
it
is
used
as
a
fumigant
under
controlled
delivery
system
of
gaseous
hydrogen
cyanide
into
an
airtight
enclosure
as
described
in
the
sodium
cyanide
label
(
SLA
CA
840006)
(
F.
Kahn,
D318020,
2/
7/
06).
HED
also
evaluated
potential
exposure
and
risk
from
cyanide
in
drinking
water
sources
in
Arizona.
Potential
sources
of
cyanide
drinking
water
contamination
in
Arizona
include
mining,
metal
finishing,
and
organic
chemical
industries.
HED
obtained
monitoring
data
on
total
cyanide
levels
in
public
drinking
water
systems
throughout
the
State
of
Arizona
from
the
Arizona
Department
of
Environmental
Quality
(
ADEQ).
ADEQ
provided
drinking
water
monitoring
data
for
a
13
year
period
­
from
January,
1993
through
June,
2006.
These
data
indicate
that
total
cyanide
concentrations
are
non­
detectable
throughout
the
monitoring
period
(
Personal
communication,
John
Calkins,
ADEQ,
7/
10/
06).
Based
on
this
information,
drinking
water
exposure
is
expected
to
be
negligible
and
was
therefore
not
assessed
for
this
TRED.

6.3
Acute
Dietary
Exposure
and
Risk
Dietary
risk
assessment
incorporates
both
exposure
and
toxicity
of
a
given
pesticide.
For
acute
assessments,
the
risk
is
expressed
as
a
percentage
of
a
maximum
acceptable
dose
(
i.
e.,
the
dose
which
HED
has
concluded
will
result
in
no
unreasonable
adverse
health
effects).
This
dose
is
referred
to
as
the
population
adjusted
dose
(
PAD).
The
PAD
is
equivalent
to
the
reference
dose
(
RfD)
divided
by
the
Food
Quality
Protection
Act
(
FQPA)
Safety
Factor.
Page
34
of
44
For
acute
exposures,
HED
is
concerned
when
estimated
dietary
risk
exceeds
100%
of
the
PAD.
References
which
discuss
the
acute
and
chronic
risk
assessments
in
more
detail
are
available
on
the
EPA/
pesticides
web
site:
"
Available
Information
on
Assessing
Exposure
from
Pesticides,
A
User's
Guide,"
6/
21/
2000,
web
link:
http://
www.
epa.
gov/
fedrgstr/
EPAPEST
2000/
July/
Day­
12/
6061.
pdf
;
or
see
SOP
99.6
(
8/
20/
99).

The
acute
dietary
exposure
assessment
for
hydrogen
cyanide
was
conducted
using
the
Dietary
Exposure
Evaluation
Model
software
with
the
Food
Commodity
Intake
Database
(
DEEM­
FCID
 
,
Version
2.03),
which
incorporates
consumption
data
from
USDA's
Continuing
Surveys
of
Food
Intakes
by
Individuals
(
CSFII),
1994­
1996
and
1998.
The
1994­
96,
98
data
are
based
on
the
reported
consumption
of
more
than
20,000
individuals
over
two
non­
consecutive
survey
days.
Foods
"
as
consumed"
(
e.
g.,
apple
pie)
are
linked
to
EPA­
defined
food
commodities
(
e.
g.
apples,
peeled
fruit
­
cooked;
fresh
or
N/
S;
baked;
or
wheat
flour
­
cooked;
fresh
or
N/
S,
baked)
using
publicly
available
recipe
translation
files
developed
jointly
by
USDA/
ARS
and
EPA.
For
chronic
exposure
assessment,
consumption
data
are
averaged
for
the
entire
U.
S.
population
and
within
population
subgroups,
but
for
acute
exposure
assessment
are
retained
as
individual
consumption
events.
Based
on
analysis
of
the
1994­
96,
98
CSFII
consumption
data,
which
took
into
account
dietary
patterns
and
survey
respondents,
HED
concluded
that
it
is
most
appropriate
to
report
risk
for
the
following
population
subgroups:
the
general
U.
S.
population,
all
infants
(<
1
year
old),
children
1­
2,
children
3­
5,
children
6­
12,
youth
13­
19,
adults
20­
49,
females
13­
49,
and
adults
50+
years
old.

For
acute
exposure
assessments,
individual
one­
day
food
consumption
data
are
used
on
an
individual­
by­
individual
basis.
The
reported
consumption
amounts
of
each
food
item
can
be
multiplied
by
a
residue
point
estimate
and
summed
to
obtain
a
total
daily
pesticide
exposure
for
a
deterministic
exposure
assessment,
or
"
matched"
in
multiple
random
pairings
with
residue
values
and
then
summed
in
a
probabilistic
assessment.
The
resulting
distribution
of
exposures
is
expressed
as
a
percentage
of
the
aPAD
on
both
a
user
(
i.
e.,
only
those
who
reported
eating
relevant
commodities/
food
forms)
and
a
per­
capita
(
i.
e.,
those
who
reported
eating
the
relevant
commodities
as
well
as
those
who
did
not)
basis.
In
accordance
with
HED
policy,
per
capita
exposure
and
risk
are
reported
for
all
tiers
of
analysis.
However,
for
tiers
1
and
2,
any
significant
differences
in
user
vs.
per
capita
exposure
and
risk
are
specifically
identified
and
noted
in
the
risk
assessment.

HED
conducted
a
somewhat
refined
probabilistic
acute
dietary
exposure
analysis
using
recently
submitted
field
trial
data
for
the
hydrogen
cyanide
DEEM
acute
analysis.
The
recently
submitted
data
for
residues
of
hydrogen
cyanide
in
orange
peel
and
orange
pulp
were
used
for
the
dietary
exposure
analysis
as
it
better
reflects
actual
residues
in
the
edible
pulp
and
peel
portions
of
the
treated
citrus.
Previously
submitted
data
provided
whole
fruit
residues
but
did
not
provide
residues
in/
on
pulp
and
peel.
Citrus
commodities
are
treated
as
non­
blended
for
this
assessment
because
fumigation
occurs
post­
harvest.
Therefore,
blending
of
treated
and
non­
treated
commodities
is
not
likely
to
occur.
Since
treated
fresh
citrus
commodities
are
non­
blended,
residue
distribution
files
(
RDFs)
created
using
field
trial
data
were
used
for
this
analysis.
Two
Page
35
of
44
RDFs
were
used,
one
for
edible
pulp
residues
and
one
for
peel
residues.
Since
there
are
so
few
commodities,
all
commodities
are
non­
blended,
and
only
narrow
range
of
residue
values
are
available
for
each
type
of
treated
commodity,
and
treated
citrus
is
destined
for
the
fresh
market
in
Arizona
only,
percent
crop
treated
information
is
not
a
factor
in
the
analysis.
Since
citrus
destined
for
the
fresh
market
only
is
fumigated,
only
fresh
citrus
commodities
were
used
in
the
dietary
analysis.
Since
citrus
is
treated
in
California
and
but
shipped
to
and
consumed
only
in
Arizona,
8
hour
residue
samples
were
not
used
the
dietary
exposure
analysis;
only
the
residue
data
for
the
24
and
48
hour
samples
were
used.
Based
on
the
new
data,
residues
included
in
the
dietary
analysis
for
edible
citrus
pulp
ranged
from
<
0.005
 
0.04
ppm
and
residues
in
citrus
peel
ranged
from
0.3
 
1.3
ppm.

The
results
of
the
acute
dietary
exposure
analyses
at
the
95th,
99th,
and
99.9th
percentiles
of
exposure
for
consumption
of
fresh
citrus
(
edible
pulp
and
peel)
are
presented
in
Tables
11
and
12.
Data
from
the
food
diaries
provided
in
the
Food
Commodity
Intake
Database
(
FCID)
can
be
used
to
characterize
assumptions
regarding
fresh
citrus
consumption
used
in
the
DEEM
analysis.
Based
on
FCID
data,
young
children
(
1­
2
years,
3­
5
years)
are
estimated
to
consume
approximately
1
orange
per
day
at
the
95th
percentile.
For
the
general
population,
95th
percentile
consumption
is
estimated
to
be
2
to
3
peeled
oranges
per
day.
As
required
in
the
HED
policy,
any
significant
differences
in
user
vs.
per
capita
exposure/
risk
should
be
specifically
identified
and
noted
in
the
risk
assessment.
A
user
is
a
survey
participant
who
consumes
a
treated
target
food
during
the
period
of
analysis.
The
per
capita
measure
estimates
exposure
risk
in
the
subpopulation
of
interest
as
a
whole,
not
just
consumers
of
the
treated
commodity.
Given
that
only
treated
citrus
commodities
are
likely
to
be
consumed
during
a
single
day,
the
period
of
analysis
for
acute
dietary
exposure,
user
exposure
is
considered
the
most
appropriate
risk
measure
for
this
analysis.
These
assessments
conclude
that
acute
dietary
exposure
estimates
are
below
HED's
level
of
concern.

Table
11.
Hydrogen
Cyanide
DEEM
Acute
Dietary
Exposure
Analysis
­
Per
Capita
Exposure
Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD.
(
95th
%)
99th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99th
%)
99.9th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99.9th
%)

General
U.
S.
Population
0.004
0.0001
1
0.0002
4
0.0004
11
All
Infants
(<
1
year
old)
0.004
>
0.0001
>
1
0.0001
1
0.0003
9
Children
1­
2
years
old
0.004
0.0001
3
0.0004
10
0.0009
23
Children
3­
5
years
old
0.004
0.0001
3
0.0003
9
0.0008
21
Children
6­
12
years
old
0.004
0.0001
2
0.0002
5
0.0005
11
Youth
13­
19
years
old
0.004
0.0001
1
0.0002
4
0.0004
10
Adults
20­
49
years
old
0.004
>
0.0001
>
1
0.0001
3
0.0003
7
Females
13­
49
years
old
0.004
>
0.0001
>
1
0.0001
3
0.0003
7
Adults
50+
years
old
0.004
>
0.0001
>
1
0.0001
2
0.0002
5
Table
12.
Hydrogen
Cyanide
DEEM
Acute
Dietary
Exposure
Analysis
­
Per
User
Exposure
Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD.
(
95th
%)
99th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99th
%)
99.9th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99.9th
%)
Page
36
of
44
Table
12.
Hydrogen
Cyanide
DEEM
Acute
Dietary
Exposure
Analysis
­
Per
User
Exposure
Population
Subgroup
aPAD
(
mg/
kg/
day)
95th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD.
(
95th
%)
99th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99th
%)
99.9th
%
ile
Exposure
(
mg/
kg/
day)
%
aPAD
(
99.9th
%)

General
U.
S.
Population
0.004
0.0001
3
0.0003
7
0.0006
16
All
Infants
(<
1
year
old)
0.004
0.0003
7
0.0005
11
0.0009
20
Children
1­
2
years
old
0.004
0.0004
9
0.0007
18
0.0014
37
Children
3­
5
years
old
0.004
0.0003
7
0.0006
15
0.0013
32
Children
6­
12
years
old
0.004
0.0002
5
0.0004
9
0.0006
14
Youth
13­
19
years
old
0.004
0.0002
5
0.0003
8
0.0005
14
Adults
20­
49
years
old
0.004
0.0001
3
0.0002
5
0.0005
12
Females
13­
49
years
old
0.004
0.0001
3
0.0002
5
0.0004
10
Adults
50+
years
old
0.004
0.0001
2
0.0001
3
0.0002
7
7.0
OCCUPATIONAL
EXPOSURE
AND
RISK
Workers
are
potentially
exposed
to
hydrogen
cyanide
from
its
use
in
post­
harvest
fumigation
of
citrus
contained
in
closed
transport
trailers.
Sodium
cyanide
is
used
only
in
California
to
control
red
scale
on
fresh
market
citrus
bound
for
Arizona
under
the
restrictions
of
the
SLN
label.
Consequently,
fumigation
of
citrus
with
hydrogen
cyanide
is
limited
to
a
single
facility
in
California.
Worker
exposure
monitoring
data
from
fumigations
conducted
at
this
facility
were
used
to
assess
occupational
exposure
and
risk
to
hydrogen
cyanide
resulting
from
citrus
fumigation.

7.1
Regulatory
Standards
The
current
Occupational
Safety
and
Health
Administration
(
OSHA)
permissible
exposure
limit
(
PEL)
for
hydrogen
cyanide
is
10
ppm
(
11
milligrams
per
cubic
meter
(
mg/
m3))
as
an
8­
hour
time­
weighted
average
(
TWA)
concentration.
The
OSHA
PEL
also
bears
a
"
skin"
notation,
which
indicates
that
the
cutaneous
route
of
exposure
(
including
mucus
membranes
and
eyes)
contributes
to
overall
exposure.
The
National
Institute
for
Occupational
Safety
and
Health
(
NIOSH)
has
established
a
recommend
exposure
limit
(
REL)
for
hydrogen
cyanide
of
4.7
ppm
(
5
mg/
m3)
as
a
short
term
exposure
limit
(
STEL)
or
level
at
which
an
unprotected
worker
can
be
exposed
for
15
minutes
without
harm.
NIOSH
also
assigns
a
"
skin"
notation
to
hydrogen
cyanide.

7.2
Exposure
Monitoring
Study
A
monitoring
study
of
worker
exposure
to
hydrogen
cyanide
was
conducted
in
1999
(
MRID
46648901)
(
D.
Jaquith,
D318017,
3/
30/
06).
The
study
monitored
air
concentrations
of
cyanide
in
the
breathing
zone
of
the
applicators
and
in
the
ambient
air
resulting
from
fumigation
of
citrus
contained
in
transport
trailers.
Monitoring
was
conducted
at
Washburn
and
Sons,
Highgrove,
CA,
the
only
operators
of
a
trailer/
truck
citrus
hydrogen
cyanide
fumigation
facility.
Air
monitoring
was
conducted
on
2
days
during
routine
fumigation
operations.
Citrus
containing
trailers
were
treated
in
a
closed
system
at
label
specified
rates.
The
trailers
were
fumigated
for
1
hour
followed
by
aeration
with
more
than
10
air
changes
for
½
to
1
hour.
Following
fumigation,
the
trailers
were
Page
37
of
44
ventilated
for
1
hour
through
a
ventilation
stack
with
a
height
of
20
feet
6
inches
at
a
rate
of
800
ft3/
minute.
A
total
of
10
fumigation/
ventilations
were
monitored
during
the
study.

Airborne
hydrogen
cyanide
concentrations
were
measured
using
Safelog
100
datalogging
monitors.
One
monitor
was
carried
in
the
breast
pocket
of
the
fumigator.
One
ambient
monitor
was
located
50
feet
from
the
trailer,
somewhat
farther
than
the
20
foot
buffer
zone
required
by
the
label.
Additional
area
monitors
were
located
downwind
at
distances
of
50,
100,
and
200
feet
from
the
trailer.
The
detection
range
was
0­
50
ppm
in
increments
of
0.1
ppm
with
+
5%
sensor
accuracy
and
<
2%
drift.
The
high
alarm
for
Hydrogen
cyanide
is
10
ppm,
the
STEL
and
TWA
Alarm
is
4.7
ppm.

Hydrogen
cyanide
levels
of
the
personal
monitor
worn
by
the
fumigator
are
presented
in
Table
13.
Exposure
was
low
and
no
alarms
were
noted
at
any
time.
Peak
1­
minute
levels
were
4.7
and
5.6
ppm
for
the
two
days.
The
peak
STEL
was
0.4
for
each
of
the
days
The
results
of
the
ambient
air
monitoring
are
presented
in
Table
14.
The
TWAs
were
all
zero.
The
peak
15
minute
STEL
ranged
from
0
to
0.6.
The
latter
was
judged
to
be
the
result
of
displacement
of
a
sunshade
during
monitoring.

Table
13.
Gas
Detection
Report
for
the
Fumigator
Hydrogen
cyanide
Levels
(
ppm)
Date
Time
Start­
Stop
#
of
Trailers
Peak(
1min)
Average
STEL1
TWA2
2/
18/
99
10:
27
am
­
5:
31
pm
3
4.7
0
0.4
0
3/
3/
99
9:
00
am
­
8:
19
pm
7
5.6
0
0.4
0
1
The
Short
Term
Exposure
Limit
(
STEL)
to
which
an
unprotected
worker
may
be
exposed
over
a
15
min
periods
2
The
time­
weighted
average
(
TWA)
is
the
average
air
concentration
taken
over
an
eight­
hour
period
Table
14.
Ambient
Air
Monitoring
Results
Hydrogen
cyanide
Levels
(
ppm)
Monitor
No.
Month
Distance
from
Trailer
(
ft)
Peak
(
1
min)
Avg
STEL
TWA
2
February
50
2.3
0
0
0
3
February
100
0.5
0
0
0
4
February
200
0.3
0
0
0
5
February
45
5.9
0
0.3
0
2
March
50
2.2
0
0
0
3
March
100
1.2
0
0
0
4
March
200
0.9
0
0.6
0
5
March
45
1
0
0.1
0
7.3
Inhalation
Exposure
and
Risk
A
NOAEL
of
65
mg/
m3
(
60
ppm)
has
been
established
based
on
a
continuous
6
hour
exposure
for
14
weeks.
Adjusted
for
occupational
exposure,
the
inhalation
exposure
endpoint
for
hydrogen
cyanide
is
50
mg/
m3
(
46
ppm).
The
target
LOC
or
MOE
for
inhalation
exposure
to
hydrogen
cyanide
is
30.
The
peak
15
minute
STEL
for
worker
exposure
from
the
monitoring
study
was
0.4
ppm
(
0.36
mg/
m3).
It
is
important
to
note
that,
based
on
the
fumigation
process
and
as
Page
38
of
44
indicated
in
the
monitoring
study,
worker
exposure
from
hydrogen
cyanide
fumigation
is
likely
to
be
short­
term
and
intermittent
rather
than
continuous.
Therefore,
use
of
an
endpoint
based
on
continuous
exposure
will
result
in
a
conservative
estimate
of
risk.
The
MOE
calculated
using
the
highest
worker
STEL
from
the
monitoring
study
is
115.
Based
on
this
analysis,
calculated
inhalation
MOEs
are
below
HED's
level
of
concern.

7.4
Dermal
Exposure
and
Risk
Sodium
cyanide
is
delivered
to
the
container
(
transport
trailer)
without
handling
by
the
fumigator
and
hydrogen
cyanide
is
produced
in
a
closed
system.
Dermal
exposure
and
risks
to
hydrogen
cyanide
residues
following
sterilization
cannot
be
fully
determined
without
further
information
regarding
the
nature
and
extent
of
post­
sterilization
activities
(
e.
g.,
post­
treatment
handling
of
citrus).
However,
based
on
the
fumigation
method
and
the
physical/
chemical
nature
of
the
fumigant,
it
is
reasonable
to
assume
that
handling
of
and
exposure
to
treated
citrus
during
poststerilization
activities
is
limited
and
dermal
exposure
is
negligible.

8.0
AGGREGATE
EXPOSURE
AND
RISK
Aggregate
exposure
is
assessed
when
there
are
potential
residential
exposures
to
the
pesticide,
aggregate
risk
assessment
must
consider
exposures
from
three
major
sources:
oral,
dermal
and
inhalation
exposures.
Since
there
are
no
residential
uses,
an
aggregate
exposure
risk
assessments
was
not
conducted.

9.0
CUMULATIVE
RISK
Section
408(
b)(
2)(
D)(
v)
of
FFDCA
requires
that,
when
considering
whether
to
establish,
modify,
or
revoke
a
tolerance,
the
Agency
consider
"
available
information"
concerning
the
cumulative
effects
of
a
particular
pesticide's
residues
and
"
other
substances
that
have
a
common
mechanism
of
toxicity."

EPA
does
not
have,
at
this
time,
available
data
to
determine
whether
hydrogen
cyanide
has
a
common
mechanism
of
toxicity
with
other
substances.
Unlike
other
pesticides
for
which
EPA
has
followed
a
cumulative
risk
approach
based
on
a
common
mechanism
of
toxicity,
EPA
has
not
made
a
common
mechanism
of
toxicity
finding
as
to
hydrogen
cyanide
and
any
other
substances
and,
hydrogen
cyanide
does
not
appear
to
produce
a
toxic
metabolite
produced
by
other
substances
which
have
tolerances
in
the
U.
S.
For
the
purposes
of
this
tolerance
reassessment
action,
therefore,
EPA
has
not
assumed
that
hydrogen
cyanide
has
a
common
mechanism
of
toxicity
with
other
substances.
For
information
regarding
EPA's
efforts
to
determine
which
chemicals
have
a
common
mechanism
of
toxicity
and
to
evaluate
the
cumulative
effects
of
such
chemicals,
see
the
policy
statements
released
by
EPA's
OPP
concerning
common
mechanism
determinations
and
procedures
for
cumulating
effects
from
substances
found
to
have
a
common
mechanism
on
EPA's
website
at
http://
www.
epa.
gov/
fedrgstr/
EPA_
PEST/
2002/
January/
Day_
16/.
Page
39
of
44
10.0
DATA
NEEDS
10.1
Residue
Chemistry
Data
Requirements
­
Storage
stability
data
for
citrus
are
required
­
Guideline
860.1380
­
Analytical
standards
for
sodium
and
hydrogen
cyanide
are
not
currently
available
in
the
National
Pesticide
Standards
Repository.
Analytical
Reference
standards
of
sodium
and
hydrogen
cyanide
must
be
supplied
and
supplies
replenished
as
requested
by
the
Repository
­
Guideline
860.1650
­
Additional
data
are
required
to
validate
newly
submitted
residue
data
(
MRID
46868001).
Residue
data
from
an
additional
two
trials
are
required
along
with
residue
data
on
whole
oranges.
A
detailed
explanation
of
the
modifications
to
EPA
335.2
along
with
validation
of
this
method
at
the
reported
LOD
of
0.01
ppm
is
required.

10.2
Toxicology
Data
Requirements
­
None.
The
classification
of
the
carcinogenic
potential
could
not
be
determined
due
to
the
absence
of
acceptable
cancer
studies
in
rats
and
mice.
However,
because
of
cyanide's
high
toxicity,
it
would
be
difficult
to
conduct
a
meaningful
cancer
study
in
rats
and
mice
over
a
twoyear
period.
Page
40
of
44
APPENDICES
1.0
GUIDELINE
TOXICOLOGY
DATA
SUMMARY
Data
requirements
(
40CFR
158.340)
for
hydrogen
cyanide
are
provided
in
the
following
table.
Use
of
new
GL
numbers
does
not
imply
that
new
(
1998)
guideline
protocols
were
used.

Technical
Test
Required
Satisfied
870.1100
Acute
Oral
Toxicity..........................................................
870.1200
Acute
Dermal
Toxicity
.....................................................
870.1300
Acute
Inhalation
Toxicity
.................................................
870.2400
Primary
Eye
Irritation
.......................................................
870.2500
Primary
Dermal
Irritation
.................................................
870.2600
Dermal
Sensitization.........................................................
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
870.3100
Oral
Subchronic
(
rodent)..................................................
870.3150
Oral
Subchronic
(
nonrodent)............................................
870.3200
21­
Day
Dermal
.................................................................
870.3250
90­
Day
Dermal
.................................................................
870.3465
90­
Day
Inhalation
.............................................................
yes
yes
no
no
yes
yes
yes
no
no
yes
870.3700a
Developmental
Toxicity
(
rodent)
.....................................
870.3700b
Developmental
Toxicity
(
nonrodent)
...............................
870.3800
Reproduction.....................................................................
yes
yes
yes
yes
yes
yes
870.4100a
Chronic
Toxicity
(
rodent)
.................................................
870.4100b
Chronic
Toxicity
(
nonrodent)
...........................................
870.4200a
Oncogenicity
(
rat)
.............................................................
870.4200b
Oncogenicity
(
mouse).......................................................
870.4300
Chronic/
Oncogenicity.......................................................
yes
yes
yes
yes
yes
no
yes
no
no
no
870.5100
Mutagenicity­­
Gene
Mutation
­
bacterial.........................
870.5300
Mutagenicity­­
Gene
Mutation
­
mammalian....................
870.5xxx
Mutagenicity­­
Structural
Chromosomal
Aberrations.......
870.5xxx
Mutagenicity­­
Other
Genotoxic
Effects
...........................
yes
yes
yes
yes
yes
yes
yes
yes
870.6100a
Acute
Delayed
Neurotox.
(
hen)........................................
870.6100b
90­
Day
Neurotoxicity
(
hen)..............................................
870.6200a
Acute
Neurotox.
Screening
Battery
(
rat)..........................
870.6200b
90
Day
Neuro.
Screening
Battery
(
rat).............................
870.6300
Develop.
Neuro.................................................................
no
no
yes
yes
no
­
­
yes
yes
no
870.7485
General
Metabolism
.........................................................
870.7600
Dermal
Penetration...........................................................
yes
yes
yes
yes
Special
Studies
for
Ocular
Effects
Acute
Oral
(
rat).................................................................
Subchronic
Oral
(
rat)........................................................
Six­
month
Oral
(
dog)
.......................................................
no
no
no
no
no
no
Page
41
of
44
2.0
NON­
CRITICAL
TOXICOLOGY
STUDIES
None
3.0
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